ENZYMES IN SIGNAL TRANSDUCTION PATHWAYS

Table of contents :




  • (non-receptor) protein serine / threonine kinases
  • (non-receptor) protein tyrosine kinases (PTK)
  • protein threonine / tyrosine kinases
  • protein histidine kinases
  • lipid kinases
  • lipid phosphatases
  • protein serine / threonine phosphatase
  • protein tyrosine phosphatase (PTP)
  • dual specificity protein serine / tyrosine phosphatase
  • protein threonine / tyrosine phosphatase
  • caspases
  • (non-receptor) guanlyate cyclases (GC)
  • adenylate cyclases (AC)
  • phosphodiesterases (PDE)
  • nucleotide metabolism
  • DNA topoisomerases
  • histone deacetylase (HD / HDAC)
  • histone acetyltransferase (HAT)
  • ATPases
  • phospholipases
  • ANRP
  • AAP
  • Ras-like superfamily
  • GNRP / GEF / GDS
  • GAP
  • GEF & GAP
  • GDI
  • eicosanoid metabolism
  • neurotransmitter anabolism
  • neurotransmitter catabolism
  • Bcl-2 family
  • cytochromes
  • ATP-binding cassette (ABC) proteins
  • matrix metalloproteinases (MMPs)


  •  

    Enzyme family
    enzyme name
    substrate(s)
    activator(s)
    inhibitor(s)

    UDP-glucose ceramide glucosyltransferase (UGCG) / ceramide glucosyltransferase / glucosylceramide synthase 
    (GCS)
    UDP-glucose + ceramide => glucosylceramide
    N-butyl-deoxynojirimycin (NB-DNJ) / miglustat / OGT 918 (Vevesca®, Zavesca® in Europe) 
    OGT2378 
    GENZ-112638ref

    ceramide kinase (CERK)ref



    mammalian target of rapamycin (mTOR)

  • 6-dimethylaminopurine 
  • sirolimus / rapamycin (Rapamune®; in drug-eluting stents sold under the trade name Cypher®) complexed to FKBP1A / FKBP12 
  • everolimus / SDZ RAD / 40-O-(2-hydroxyethyl)-rapamycin (Certican®)
  • temsirolimus / CCI-779 (Torisel®)
  • deforolimus / AP23573 
  • zotarolimus (in drug-eluting stents sold under the trade name Endeavor® and ZoMaxx®)
  • biolimus (in drug-eluting stents sold under the trade name Axxess®)
  • umirolimus
  • ridaforolimus / AP23573
  • ABI-009
  • TOP-216
  • BEZ-235
  • NVP-BEZ235
  • ATP-competitive mTOR inhibitors : AZD8055

  • IMP dehydrogenase (IMPDH) 2, a de novo guanine (Gua) ribo- and 2'-deoxyribonucleotides synthesis enzyme expressed in T- and B-lymphocytes and up-regulated upon cell activation

    less potent on IMPDH 1, expressed in most cell types. 
     
  • mycophenolate mofetil (MFF) / RS-61443 (Cell-cept®; Myfortic® is the enteric-coated formulation designed to protect the upper G-I tract) is the 2-morpholinoethyl ester prodrug of mycophenolic acid (MPA)


  • Catabolyzed to the inactive mycophenolic acid glucuronide (MPAG)
  • mizoribine (MZB)
  • VX-497
  • ribavirin
  • AVN944

  • dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pathway of pyrimidine synthesis

  • leflunomide (Arava®) => A77 1726 is noncompetitive versus ubiquinone 
  • polyporic acid
  • brequinar / DUP-785 is a competitive inhibitor versus ubiquinone
    • 2-phenyl 5-quinolinecarboxylic acid (PQC), the core moiety of brequinar, also shows competitive inhibition versus ubiquinone
  • HR325
  • KF20444 
  • barbituric acid (a competitive inhibitor versus DHO)

  • purine nucleoside phosphorylase (PNP)

    forodesine / immuncillin H / BCX-1777 / immucillin hypoxanthine / [1(S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol]

    betaine-homocysteine-S-methyltransferase (BHMT)

    S-(d-carboxybutyl)-DL-homocysteine (CBHcy)ref
    secretase alpha-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-alpha convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of alpha-secretaseref


    beta-secretaseb-site APP-cleaving enzyme 1 (BACE1) and BACE2


    gamma-secretase complex
    • Nicastrin (Nct) / APH2, APH-1A/APH-1B, and PSENEN / PEN-2, when combined with a heterodimer of endoproteolysed presenilin (presenilin 1 (PS1) and PS2) fragments, form a stable, catalytically active, high-molecular-mass protein complex. This unusual aspartyl protease is the founding member of a novel class of proteases that carry out intramembrane cleavage, resulting in peptide-bond hydrolysis within the hydrophobic environs of the lipid bilayer


    gamma-secretase inhibitors (GSI) : 
  • LY450139 



  • polo-like kinase (PLK) 1


    volasertib / BI 6727
    PLK2


    PLK3


    PLK4

    CFI-400945
    protein serine / threonine kinases Raf1

    BAY 43-9006 / sorafenib (Nexavar®) (also inhibits RTKs FLT-3, VEGFR2 and c-KIT)
    BRAF


    vemurafenib / PLX4032 (Zelboraf®)
    dabrafenib / GSK2118436 (Tafinlar®)
    GSK-3b

    6-dimethylaminopurine 
    6-bromoindirubin-3'-oxime (BIO) 
    Li+
    CDK1 & CDK2

    6-dimethylaminopurine 
    flavopiridol / alvocidib 
    UCN-01 / 7-hydroxystaurosporine 
    seliciclib (CYC202; R-roscovitine) 
    indirubin
    CDK9

    6-dimethylaminopurine 
    flavopiridol / alvocidib
    p70S6K

    6-dimethylaminopurine
    MAPKKKs

    6-dimethylaminopurine
    p38 / MAPK1 / ERK2

    6-dimethylaminopurine ; 
    SB202190 ; 
    SB203580 ; 
    SB281832 ; 
    PD169316 ; 
    RWJ-67657 ; 
    BiRB0797 ; 
    Ro320-1195 
    VX-745 
    SCIO-469
    p44 / MAPK3 / ERK1

    6-dimethylaminopurine 
    U0126
    RhoA kinase (ROCK1)

    6-dimethylaminopurine 
    Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4- (1-aminoethyl)cyclohexanecarboxamide]
    PKA : C2R
    • catalytic subunit (C) : except that for mCb3, it is miristoylated but it doesn't anchor it on the cytoplasmic side; they can phosphorylate RII subunits.
      • Ca1 (it can undergo autophosphorylation)
      • Ca2 (inactive)
      • Ca-s
      • bCb1 (it can undergo autophosphorylation)
      • bCb2
      • mCb1
      • mCb2
      • mCb3
      • Cg (it doesn't bind PKI; it can undergo autophosphorylation)
      • PrkX1
    • regulatory subunit

    Sp-8-Br-cAMPS ; 
    dibutiryl-cAMP (dbcAMP) 
    H8 (N-(2- methylaminoethyl) -5-isochinoline sulfonamide. A compound derived from calmodulin antagonists that does no longer possess calmodulin -inhibitory activity.) 
    H89 
    6-dimethylaminopurine
    PKB

    6-dimethylaminopurine 
    IL-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate 
    perifosine [octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate]
    PKC (PS-dependent) 
    • DAG- and Ca2+-dependent or conventional (cPKC)
    • DAG-dependent and Ca2+-independent or novel (nPKC)
    • DAG- and Ca2+-independent, PI-3,4,5-P3-dependent or atypical (aPKC)
    • PKCm / PKD
    • PRK / PKN 1, 2 and 3

    phorbol esters
    bryostatins
    6-dimethylaminopurine 
    calphostin C
    staurosporine
    UCN-01 / 7-hydroxystaurosporine 
    ruboxistaurin mesylate (PKCb-specific) 
    Go6976 
    K-252a 
    H7 
    GF 109203X 
    rottlerin 
    enzastaurin (LY317615.HCl) 
    sotrastaurin (AEB-071) (source : Novartis) 
    PKC412
    DNA-PK

    6-dimethylaminopurine
    CaMK

    6-dimethylaminopurine
    (non-receptor) protein tyrosine kinases (PTK) Janus family (so named as they also have an inactive Ser/Thr kinase domain) 

    JAK2 selective (not selective for JAK2-V617F) :
    • INCB018424 / ruxolitinib (Jakafi©) (source : Incyte/Novartis)ref
    • XL019 (source : Exelixis)
    • TG101348 / SAR302503 (source : TargeGen)
    • NS-018
    • BMS911543
    SU5146
    AZD1418 (JAK1/2)
    CEP701 (JAK2/3)
    CYT387 (JAK1/2, Tyk2)
    tasocitinib / CP690550 / tofacitinib
    SB1518 / pacritinib (JAK2, Tyk2)
    LY2784544 is a small molecule selective mutant JAK2 inhibitor
    Src family (in some RCTKs the SH4 domain is also palmitoylated) 

    PP2, middle t antigen from SV40


    CGP57148
    imatinib mesylate / STI 571 (Gleevec / Glivec©)
    dasatinib / BMS-354825 (Sprycel©)
    nilotinib (Tasigna©)
    bosutinib / SKI-606 (Bosulif©)
    ponatinib (Iclusig©)
    bafetinib / INNO-406






    A-770041 (Lck-selective)
    Bruton's kinase (Btk)


    ONO-WG-307
    LFM-A13
    dasatinib (Sprycel©)
    CC-292
    ibrutinib / PCI-32765 (Imbruvica©)
    Interleukin-2 Inducible Kinase (ITK)


    protein threonine / tyrosine kinases MAPKK / MEK

    UO126
    trametinib (Mekinist©)
    PD98059 
    LF from Bacillus anthracis
    wee1


    mik1


    protein histidine kinases (only in plants and Bacteria) ETR1, ETR2, EIN4, ERS1, ERS2 (coupled to ethylene receptor)


    CRE1 / AHK4 (coupled to cytokinin receptor)


    CKI1, CKI2 (coupled to cytokinin receptor)


    ATHK1 (osmosensor)


    lipid kinases PI3K
  • class I (+ RasBD)
    • subclass IA (stimulated also by FRP)
      • p110a => PI3Ka
      • p110b => PI3Kb
      • p110d => PI3Kd
      adapters or regulatory subunits : 
    • subclass IB (stimulated by Gbg subunits)
    • adapter or regulatory subunit : 
  • class II (+ C2 domain)
  • class III :
    • VPS34

    • adapter or regulatory subunit : 

    middle t antigen from SV40 LY294002 
    radicicol 
    wortmannin
    idelalisib / GS-1101 / CAL-101
    NVP-BKM120
    diacylglycerol kinase (DAGK) 

    R59022 
    sphingosine kinase 1 (SphK1)
    sphingosine kinase 2


    N,N-dimethylsphingosine (DMS) 
    dihydro-sphingosine (DHS)
    lipid phosphatases IP phosphatase

    Li+
    protein serine / threonine phosphatase PP1 / PPI glycogen phosphorylase (inhibited) 
    p105Rb (inhibited) 
    p80cdc25 (inhibited) 
    eIF2a (activated) 
    glycogen synthase (activated) 
    IkBa (activated) 
    X (activated or inhibited)

    tautomycin
    tautomycetin (TMC)
    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-
    okadaic acid (weak inhibition) 
    microcystin-LR
    PP2A / PPIIA

    tautomycin
    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-
    okadaic acid (strong inhibition) 
    small t antigen from SV40
    calyculin A
    microcystin-LR
    PP2B / PPIIB / PP3 / PPIII / calcineurin (subunit A / catalytic : a, b or g; subunit B / regulatory : I or II; Ca2+CaM-dependent) T lymphocytes
    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-
    cyclosporine A complexed to cyclophilin 40 or neurophilin 
    tacrolimus (acronym for Tsukuba macrolide immunosuppressive) (FK506®) (from Streptomyces tsukubaensis) complexed to FKBP1A / FKBP12 or FKBP4 / FKBP52
    PP2C / PPIIC


    PP4 / PPIV

    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    PP5 / PPV

    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    PP6 / PPVI

    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    PP7 / PPVII

    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    protein tyrosine phosphatase (PTP) SHP-1 / PTP-1C / hematopoetic cell phosphatase (HCP) / SHPTP1 / SHP / PTPN6 

    sodium stilbogluconate (SSG) 
    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    SHP-2 / PTP-2C / Syp / PTP-1D / SH-PTP2 / PTPN11

    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    hPTP1E / PTPBAS / FAP1 
    PTP2E (Rattus norvegicus
    R-PTP y


    iodoacetic acid 
    sodium orthovanadate 
    sodium pervanadate (VO43-)
    dual specificity protein serine / tyrosine phosphatase DUSP1 / MKP1 / PTPN10
    DUSP2 / PAC1
    DUSP3 / VHR
    DUSP4 / MKP2
    DUSP5
    DUSP6 / MKP3
    DUSP7
    DUSP8
    DUSP9
    DUSP10
    DUSP11
    DUSP12
    DUSP13
    DUSP14
    DUSP15
    DUSP16
    DUSP17 / DUSP19


    VO43-
    protein threonine / tyrosine phosphatase Cdc25

    VO43-
    caspases caspase 1 / interleukin-1 converting enzyme (ICE) : 2 20-kDa and 2 10-kDa subunits (monocytes, neutrophils, resting and activated T lymphocytes, placenta tissue and several B-lymphoblastoid cell lines) pro-IL-1b and pro-IL-18
    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD) 
    crmA from cowpox virus
    P35 from Baculovirus spp. 
    pralnacasan
    caspase 2

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 3 poly (ADP-ribose) polymerase (PARP)
    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 4

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 5

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 6

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 7

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 8

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD) 
    Cbz-Leu-Glu-Thr-Asp(OMe) -fluoromethylketone (zLETD)
    caspase 9

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD) 
    Cbz-Leu-Glu-His-Asp(OMe) -fluoromethylketone (zLEHD
    caspase 10

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 11

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 12

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 13

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    caspase 14

    Cbz-Val-Ala-Asp(OMe) -fluoromethylketone (zVAD)
    (non-receptor) guanlyate cyclases (GC) guanlyate cyclase 1A2
    YC-1 
    isoliquiritigenin
    1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) 
    N-methylhydroxylamine
    adenylate cyclases (AC) AC1 (+ Gas, PKC, Ca2+CaM ;- Gai, Ga0, Gaz, b5g2, b1g2, Ca2+
    AC2 (+ : PKC; - : b5g2, b1g2
    AC3 (+ : PKC, Ca2+CaM ; - : Gai, Ca2+
    AC4 (+ : ; - : PKC) 
    AC5 (+ : PKC; - : PKA, Ga0, Gai, Gaz, Ca2+), 
    AC6 (+ : ; - : PKA, Ga0, Gai, Ca2+
    AC7 (+ : PKC, Ca2+CaM ; - : ) 
    AC8(+ : ; - : ) 
    AC9 (+ : ; - : Ca2+)
    ATP => cAMP + PPi forskolin
    forskolin
    forskolin
    forskolin
    forskolin
    forskolin
    forskolin
    forskolin
    /

    phosphodiesterases (PDE) (they all are also inhibited by xanthines (e.g. 
  • aminophylline
  • pentoxyphylline (Trental©
  • propentophylline (Karsivan©

  • ... are inhibitors of TNF-a release in monocytes activated by AGEs) and methylxanthines (e.g. 
  • caffeine / teine
  • teophylline
  • teobromine
  • diphylline
  • enprofylline
  • papaverine )

  • ..., but at concentrations >> those acting on P1 purinoceptors)
    PDE1A
    PDE1B
    PDE1C
    PDE2A
    PDE3A
    PDE3B
    PDE7A
    PDE8A
    PDE9A
    cGMP > cAMP 
    cGMP > cAMP 
    cGMP and cAMP 
    cGMP and cAMP 
    cGMP and cAMP 
    cGMP and cAMP 
    cAMP 
    cNMP 
    cAMP 

    cAMP 
    cAMP 
    cGMP

    vinpocetine (Cavinton®, Remedial®, and Vincaton®
    EHNA 
    milrinone (Primacor®
    inamrinone (Inocor®, Inamrinone Injection®) / amrinone (Amrinone lactate®), SelCIDs
    enoximone (Perfane®
    lixazinone / RS-82856 
    imadozan 
    cilostamide 
    rolipram 
    zaprinast 
    3-isobutyl-1-methylxanthine (IBMX) 
    D-22888 (type IV) 
    zardaverine (type III and IV) 
    vesnarinone / OPS 8212 (Arkin-Z®, Otsuka®
    pimobendan 
    levosimendan (Simdax®)
    BMY 20844 
    RA233 
    KF19514 (type I and IV) 
    anagrelide / BL-4162A (Agrylin®, Xagrid®, Thromboreductin®) => 2-amino-5,6-dichloro-3,4-dihydroquinazoline / RL603 
    9-(tetrahydro-2-furyl) adenine
    PDE4A
    PDE4B
    PDE4C
    PDE4D


    cilomilast (Amiflo®

    roflumilast 

    imidazo[1,2-a]quinoxalinesref
    PDE5A

    sildenafil citrate (Revatio®, Viagra®, Vigrex®) (strong inhibitor) 
    tadalafil (Cialis®
    vardenafil (Levitra®, Nuviva®
    DA-8159
    PDE6A (photoreceptors)

    sildenafil citrate (Viagra®, Vigrex®) (weak inhibitor)
    nucleotide metabolism hypoxanthine/guanine phosphoribosyltransferase (HGPRT / HPRT) 


    thymidine kinase 


    deoxyguanosine kinase


    deoxycytosine kinase


    dihydrofolate reductase (DHFR)

  • methotrexate (MTX) / amethopterin sodium (Folex©, Mexate©, Methotrexate®, Rheumatrex©, ...)
  • aminopterin sodium (Aminopterin Sodium©
  • edatrexate / 10-ethyl,10-deaza aminopterin 
  • lometrexol 
  • pralatrexate (PDX) (Folotyn©; source : Allos Therapeutics, Inc.) was rationally designed for improved transport into tumor cells via the reduced folate carrier (RFC-1), and greater intracellular drug retention
  • raltitrexed / ZD1694 (Tomudex©) : intracellularly is polyglutamated to its active form which can be retained in cells for prolonged periods.
  • pemetrexed / multitargeted antifolate (MTA) / LY231514 (Alimta©) for NSCLC, malignant mesothelioma, and other solid tumors
  • trimetrexate (Neutrexin©)
  • adenosine deaminase (ADA)

  • tacrine (Cognex©
  • pentostatin / 2'-deoxycoformycin (Nipent©
  • cladribrine / 2-chlorodeoxyadenosine (2-CdA) (Leustatin©
  • fludarabine (Fludara©
  • erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA)
  • xanthine oxidase (homodimer; converted to xanthine oxidase by irreversible proteolytic modification or reversible thiol oxidation)

    allopurinol (Allgoric©, Allorin©, Cyploric©, Lopurin©, Zyloric©, Zyloprim©) => oxypurinol 
    febuxostat / TMX-67
    ribonucleotide reductase 

    hydroxyurea / hydroxycarbamide  (Hydrea©, Oncocarbide©
    didox / 3,4-dihydroxybenzohydroxamic acid 
    trimidox / 3,4,5-trihydroxybenzamidoxime
    DNA topoisomerases DNA topoisomerase I / Scl-70

    camptothecin derivatives
    • topotecan (Hycamtin©)
    • irinotecan / CPT-11 (Camptosar©) => SN-38 
    • DTS-108 => SN-38
    • 9-nitrocamptothecin (9NC)
    • 9-aminocamptothecin (9-AC)
    • 10,11- methylenedioxycamptothecin 
    • chimmitecan
    DNA topoisomerase II / DNA girase (p170a or p180b)

    epipodophyllotoxins (synthetic analog of podophyllotoxin
    • teniposide / VM-26 (Vumon©)
    • etoposide / VP-16-213 (Vepesid©, Toposar©, Etopophos©)
    • podophyllin
    • podofilox (Condylox®)
    actinomycin D / dactinomycin (antibiotic) (Cosmegen©
    ICRF-154 
    ICRF-193 
    bleomycin (antibiotic) sulfate (Blenoxane©
    acutissimin A
    lucanthone 
    acridine derivatives : 
    • amsacrine (AMSA PD©)
    anthracycline antibiotics : 
    • aclacinomycin A (aclarubicin)
    • AD-32
    • annamycin (liposomal : Aronex©)
    • carminomycin (Carubicin©)
    • daunorubicin / daunomycin (DNM) / rubidomycin hydrochloride / NSC-82151 (Cerubidine©) => daunorubicinol
      • pegylated liposomal daunorubicin (DaunoXome©)
    • DTS-201 (source : Diatos SA) : reactivation of doxorubicin occurs extracellularly in the tumor through enzymatic cleavage of the peptide by at least two enzymes: CD10 (Neprilysin / CALLA) and Thimet Oligopeptidase (TOP). They produce two intermediate metabolites Ala-Leu-Dox and Leu-Dox which enter stromal and tumor cells and are converted into free doxorubicin hydrochloride / NSC-123127 (Adriamycin©, Rubex©, ...; Pharmacia and Upjohn; Peapack, NJ; 
      • liposomal doxorubicin / TLC D-99 (Evacet©)
      • pegylated liposomal doxorubicin (PLD) : Caelyx©, Doxil©, Doxilen©, DOX-SL©, LipoDox©, Myocet©; injections are less cardiomyotoxic
      • ThermoDox© (source : Celsion Corp.) : is a temperature-sensitive liposomal encapsulation activated by radio frequency ablation (RFA), which allows focused delivery of the drug to the liver tumor lesions
    • 4'-iodo-4'deoxydoxorubicin
    • epirubicin / 4'-epidoxorubicin (Ellence©, Pharmacia and Upjohn, Portage, MI; Farmorubicin©) is  the only anthracycline able to form glucuronides
    • esorubicin 
    • idarubicin (Idamycin®, Zavedos®) => idarubicinol 
    • mitoxantrone (an anthracenedione) (Novantrone©)
    • nemorubicin / MMDX
    • pirarubicin can be transformed into doxorubicin itself.
    • pixantrone (BBR 2778) (aza-anthracenedione)
    • sabarubicin / MEN-10755 (the first disaccharide anthracycline)

    • valrubicin (Valstar©)
    • variamycin B 
    • zorubicin (Rubidazone©)
    • RTA 401
    • RTA 402
    • RTA 744 (source : Reata Pharmaceuticals, Inc.)
    • KRN-8602
    • PNU-159568
    • pyrromycin
    • musettamycin
    • marcellomycin
  • amonafide (Xanafide©; source : Antisoma)
  • histone deacetylase (HD / HDAC)
  • class I :
  • histone deacetylase 1 (HDAC1)
  • Rpd1 (it binds Sin3 corepressor and Ume6) 
  • HDAC2
  • HDAC8
  • HDAC11
  • class II :
  • HDAC4 and HDAC5
  • HDAC6
  • HDAC7
  • HDAC9
  • HDAC10
  • class III


  • HDAC inhibitors (HDIs)
    • short chain fatty acid 
      • sodium butyrate (NaB)
      • phenylbutyrate
      • pivaloyloxymethyl butyrate (Pivanex©, AN-9) (source : Titan)
      • valproic acid (VPA) (Depakin©, Depakin Chrono©, PEAC minitablets©; source: TopoTarget A/S)
    • second generation HDI :
      • hydroxamic acids :
        • trichostatins
          • trichostatin A (TSA)
        • SAHA and its derivatives
          • vorinostat / suberoylanilide hydroxamic acid (SAHA) / NVP-LAQ824 (unselective) (source : Merck & co)
          • suberic bishydroxamic acid (SBHA)
        • oxamflatin
        • azelaic bishydroxamic acid (ABHA)
        • m-carboxycinnamic acid bis-hydroxamide (CBHA)
        • scriptaid (SB-556629)
        • pyroxamide
        • propenamides
        • aroyl pyrrolyl hydroxyamides
      • amides :
        • MS275 / N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide (HDAC1 and HDAC3)
        • MethyGene
        • CI994 (HDAC1 and HDAC3) (source : Pfizer)
    • epoxyketone-containing cyclic tetrapeptides :
      • trapoxins
      • HC-toxin
      • chlamydocin
      • diheteropeptin
      • WF-3161
      • Cyl-1 and Cyl-2
    • non-epoxyketone-containing cyclic tetrapeptides :
      • romidepsin / FK228 / bicyclic depsipeptide FR 901228 (source : Gloucester Pharmaceuticals)
      • cyclic-hydroxamic-acid-containing peptides (CHAPs)
    • miscellaneous structures
      • depudecin
      • tubacin
      • organosulfur compounds
    • second generation HDAC inhibitors with the hydroxamate and benzamide head group
      • panobinostat / LAQ824/LBH589 inhibits HDAC6 / tubulin deacetylase (TDAC) (unselective) (source : Novartis)
      • MGCD0103 (source : Pharmion Corporation and MethylGene, Inc) (HDAC1 and HDAC3)
    • belinostat / PXD101 (CuraGen, TopoTarget)
    • NVP-LAQ824 (Novartis)
    • ITF2357 / givinostat (Italfarmaco)
    SIRT1 / Sir2a p53 resveratrol
    histone acetyltransferase (HAT) p300 / CBP


    TAFII250


    GRIP


    GCN5


    PCAF


    pCIP


    SRC-1


    Tip60


    ATPases F0F1 ATPase

    oligomycin
    myosin ATPase

    butanedione monoxime (BDM)
    H+ / K+ ATPase (a subunit : gastric or nongastric ; b subunit) (lumenal membrane of parietal cells in stomach)

    proton pump inhibitors (PPI) : prodrugs activated at pH 1.0 inside the canaliculus of a parietal cell, faster than their serum elimination rate 
    • esomeprazole / S-omeprazole (Nexium®)
    • lansoprazole (Prevacid®, Zoton®) binds to cys321, 813 (or 822) and 892
    • omeprazole (racemic) (Antra®, Gastroloc®, Mopral®, Omepral®, Losec® MUPS (Multiple Unit Pellet System) tablets, Prilosec®) binds covalently to 2 cysteine residues at positions 813 (or 822) and 892
    • pantoprazole (Protium®, Protonix®) binds to cys813 and 822
    • rabeprazole (Aciphex®)
    3 Na+ / 2 K+ ATPase

    palytoxin
    cardiac glycosides (agonists of ouabain-like endogenous factors) : 
    phospholipases phospholipase A1 (PS-specific) removes FA in sn-1 from 1,2- diacylglycero phospholipids

    phospholipase A2
    mellitin
    mepacrine 
    4-Br- phenacylbromure
  • Bi 
  • 4-bromophenacylbromide
  • A-002 (1-H-indole-3-glyoxamide, varespladib methyl; Anthera Pharmaceuticals, San Mateo, CA, USA), is a novel selective sPLA2 inhibitor in human beings with specificity towards sPLA2-IIA (50% inhibitory concentration [IC50] 9–14 nmol/L), sPLA2-V 77 nmol/L), and sPLA2-X (IC50 15 nmol/L) enzymesref
  • phospholipase B


    phospholipase Cb (activated by GqPCRs; found only in Metazoa


    phospholipase Cg (activated by RTKs; found only in Metazoa


    phospholipase Cd1 (activated by Ca2+; found only in Metazoa, plants and yeasts, no PH domain
    phospholipase Ce



    PC-specific phospholipase D1 (PC-specific, PI-4,5-P2 stimulated, oleate inhibited; found in all Eukarya
    GPI-specific phospholipase D1
    phospholipase D2



    ANRP GrpE


    AAP DnaJ


    Ras-like superfamily Arf family  Rap family 
    Rab family 
    Rho family  Rac family 
    Ran family 
    Ras family 


    TAT-C3
    GNRP / GEF / GDS Dbl 
    TIAM1
    GRF1 (Ca2+-CaM-dependent) 
    GRF2 / Epac / C3G
    EF-Ts
    eIF2B  RCC 
    Smg25 
    SOS1
    VAV1
    VAV2
    VAV3



    GAP Rho/Rac GAP 
    RhoGAP1 / p50
    RhoGAP4 / p115
    RhoGAP5 / p190
    RhoGAP6 (5 isoforms) 
    chimerin 1 / n-chimaerin
    chimerin 2 / b chimaerin
    Rap1-GAP 
    RASA1 / p120GAP
    RASA2 / RasGAP 2
    IQGAP-1 
    NF1 / neurofibromin 1
    IRA1 
    IRA2
    Rho, Rac 
    Rho 
    Rho 
    Rho 
    RhoA 
    Rac 
    Rac 
    Rap1 
    Ras 
    Ras 
    Ras 
    Ras 
    Ras 
    Ras


    GEF & GAP BCR (also Ser/Thr kinase) Rho / Rac

    GDI RhoGDIa Rho

    RhoGDIb


    RhoGDIg




    membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) fatty acid cyclooxygenase (COX) => PGH synthase (PGHS) 1 (active site : Val; monotopically inserted in the ER and nuclear membrane with the substrate-binding pocket precisely orientated to take up released arachidonic acid, constitutive) 
    • COX-1 (GI tract, kidney, platelets)
    • partial COX-1 (PCOX-1)
    • COX-3 (GI tract, heart and aorta)
    Can form homodimers or heterodimers with COX-2ref


    5,8,11,14-eicosatetraynoic acid 
    nonsteroidal antiinflammatory drugs (NSAIDs)
    • alkanones
      • nabumetone (Relafen®)
    • tenidap (Enablex®
    • azapropazone / apazone (Rheumox®)
    • propacetamol is a pro-drug of paracetamol and was available in a parenteral form for many years (Pro-Dafalgan®). 2g propacetamol is hydrolysed to 1g paracetamol
    • salicylates 
      • salicylic acid choline (Arthropan®), magnesium (Magan®), or both (Buf-Puf®, Trilisate®, ...)
      • acetylsalicylic acid (ASA) (irreversible inhibitor by covalently acetylating Ser529) (Ascriptin®, Aspirin®, Aspirinetta®, Aspisevt®, Cardioaspirin®, Empirin®, Ecotrin®, Entrophen®, Genuine Bayer®, Halfprin®; Aggrenox® in combination with dipyridamole; Talwin Compound® in combination with pentazocine; Percodan®, ... in combination with oxycodone)
        • lysine acetylsalicylate (Aspegic®, Aspidol®, Cardirene®, Flectadol®) : less gastrolesive (basic salt)
      • benorilate
      • diflunisal (Dolobid®)
      • mesalamine / 5-aminosalicylic acid (Asacol®, Claversal®, Salofalk®, Salofalk® Granu-Stix®, Pentacol®, Pentasa®, Rowasa®)
      • methyl salicylate
      • olsalazine (Dipentum®) : 2 molecules of mesalamine bound together with an azo bond
      • salsalate / salicylsalicylic acid (Disalcid®, Salflex®)
      • sulfasalazine / salicylazosulfapyridine
      • choline magnesium trisalicylate (Trilisate®)
    • acetic acids 
      • phenylacetic acids
        • alclofenac (Prinalgin®)
        • diclofenac (Cataflam®, Voltarin®, Voltarin-XR®, Voltaren®, Arthrotec®(together with misoprostol))
        • fenclofenac / 2-(2,4-dichlorophenoxy)

        • phenylacetic acid (Flenac®
        • tolmetin (Tolectin®)
        • ketorolac (Acular®, Lixidol®, Toradol® or 3 mg nasal spray / ROX-888)
      • carbo- and heterocyclic
        • acermetacin (Emflex®)
        • etodolac (Lodine®, Lodine XL®)
        • indometacine / indomethacin (Imet®, Indocid®, Indocin®, Indocollirio®, Indom®, Indoxen®, Indoxen forte®, Liometacen®, Metacen®; Difmetre®, Difmetre mite® in combination with caffeine and prochloperazine)
        • oxaprozin (Daypro®)
        • sulindac (Clinoril®)
    • propionic acids 
      • benoxaprofen (Bexopron®)
      • carprofen (Rimadyl®)
      • dexibuprofen (Seractil®)
      • fenbufen (Cinopal®)
      • fenoprofen (Nalfon®)
      • flurbiprofen (Ansaid®, Ocufen®)
      • ibuprofen (Advil®, Buscofen®, Brufen®, Ibifon®, Ibren®, Ibuphil®, Ibuprin®, Ibuprohm®, Iburam®, Ibu-tab®, Ibutop®, Motrin®, Moment®, Neocybalgin®, Nuprin®, Cibalginadue®)
      • indobufen (Ibustrin®)
      • ketoprofen (Fastumgel®, Orudis®, Oruvail®)
      • naproxen (Aleve®, Anaprox®, Naprosyn®; Trexima® in combination with sumatriptan)
      • oxaprozin (Daypro®)
      • pirprofen
      • suprofen (Profenal®)
      • tiaprofenic acid (Surgaml®)
    • fenamates / N-phenylanthranilic acids 
      • flufenamic acid
      • meclofenamic acid (Arquell®, Movens®)
      • mefenamic acid (Ponstel®)
    • pyrazolones 
      • aminopyrine => ampyrone
      • antipyrine (Auralgan® in combination with benzocaine)
      • dipyrone / methamizole (Novalgina®)
      • oxyphenbutazone (Tandearil®)
      • phenylbutazone (Alindor®, Alkabutazona®, Alqoverin®, Anerval®, Anpuzone®, Antadol®, Anuspiramin®, Arthrizin®, Artrizin®, Artrizone®

      • Artropan®, Azdid®, Azobutil®, Benzone®, Betazed®, Bizolin 200®, B.T.Z.®, Butacote®, Butacompren®, Butadion®,  Butadiona®, Butadione®, Butagesic®, Butalgina®, Butalan®, Butalidon®, Butaluy®, Butaphen®, Buta-Phen®, Butapirazol®, Butapyrazole®, Butarecbon®, Butartril®, Butartrina®, Butazina®
        Butazolidin®, Butazolidine®, Butazona®, Butazone®, Butidiona®, Butiwas-simple®, Butone®, Butoz®, Butylpyrin®, Buvetzone®, Buzon®, Chembutazone®, Digibutina®, Diossidone®, Diozol®, Diphebuzol®, Diphenylbutazone®, Ecobutazone®, Elmedal®, Equi Bute®, Eributazone®, Esteve®, Febuzina®, Fenartil®, Fenibutasan®, Fenibutazona®, Fenilbutazona®, Fenylbutazon®, Fenilbutina®, Fenilbutine®, Fenibutol®, Fenilidina®, Fenotone®, Flexazone ®
        G 13,871®, IA-But®, Intalbut®, Intrabutazone®, Ipsoflame®, Kadol®, Lingel®, Malgesic®, Mephabutazone®, Merizone®, Nadazone®, Nadozone®, Neo-Zoline®, Novo-phenyl®, Phebuzin®, Phebuzine®, Phen-Buta-Vet®, Phenbutazol®, Phenopyrine®, Phenylbetazone®, Phenylbutaz®, Phenylbutazonum®, Phenyl-mobuzon®, Pirarreumol B®, Praecirheumin®, Pyrabutol®, Pyrazolidin®, Rectofasa®, Reudo®, Reudox®, Reumasyl®, Reumazin®, Reumazol®, Reumune®, Reupolar®, Robizon-V®, Rubatone®, Scanbutazone®, Schemergin®, Shigrodin®, Tazone®, Tetnor®, Tevcodyne®, Therazone®, Ticinil®, Todalgil®, Uzone®, VAC-10®, Wescozone®, Zolaphen®, Zolidinum®,) 
      • propyphenazone / propifenazone / 4-isopropylantipyrine / isopropylphenazone

      •  (Cistalgan® in combination with flavoxate
    • enolic acids 
      • oxicam 
        • ampiroxicam
        • cinnoxicam (Sinartrol®)
        • droxicam
        • isoxicam
        • lornoxicam (Xefo®)
        • meloxicam (the one with the lowest COX-2 IC50 / COX-1 IC50 rate, so usable as a COX-2 selective inhibitor) (Mobic®)
        • piroxicam (Feldene®)
        • pivoxicam
        • sudoxicam
        • tenoxicam (Tobitil®)
    • COX-inhibiting nitric oxide-donating (CINOD)
    fatty acid cyclooxygenase 2 (COX2) / PGH synthase 2 (PGHS2) (active site : Ile; monotopically inserted in the ER and nuclear membrane with the larger substrate-binding pocket precisely orientated to take up released arachidonic acid) => 
    • COX-2b (inducible)
    • COX-2 (constitutive : macula densa, thick ascending limb of Henle loop, podocytes, interstitial papillary cells of kidneys, certain brain regions => involved in renal water and electrolyte balance, gastric cytoprotection, and platelet aggregation)
    • COX-2 (inducible by various inflammatory insults in monocytes or mast cells or by shear stress in endothelium)
    Can form homodimers or heterodimers with COX-1ref


    COX-1 antagonists
  • acetanilide => p-aminophenol => phenacetin / acetophenetidin => acetaminophen / paracetamol / N-acetyl-p-aminophenolref (Acetanol®, Liquiprin®, Panadol®, Tachipirina®, Tylenol®; Perfalgan® i.v.; Talcen® in combination with pentazocine; Percocet® and Tylox® in combination with oxycodone; Co-efferalgan® and Tachidol® in combination with codeine; Mersyndol®

  • in combination with codeineand doxylamine; Algosil®, Antinevralgico Knapp®, Antireumina®, Drin®, Neocibelgina®, Neonevral®, Neonisidina®, Verdal® in combination with acetylsalicylic acid and caffeine) (on COX-2b only: antipyretic but not antiinflammatory as WBC-derived peroxides inhibit it) 
    NS-398 
    DFP [3-(2-propyloxy) -(4-methyl-sulphonylphenyl)- (5,5-dimethyl)-furanone] 
    COX-2 selective inhibitors (CSI) block the cyclooxygenase activity of PGHS2, but do not affect the associated peroxidase function 
    • sulfonanilides
      • nimesulide (Aulin®)
    • SC-58125 / SC-57666 
    • BF-389 
    • L743337 
    • flosulide 
    • indole acetic acids 
      • etodolac (Lodine®)
    • coxibs :
      • 1st generation coxibs :
        • diaryl-substituted pyrazoles 
          • celecoxib (Celebrex®)
          • OSU03012
        • diaryl-substituted furanones 
          • rofecoxib (Arofexx®, Vioxx®)
      • 2nd generation coxibs :
        • valdecoxib (Bextra®)
        • etoricoxib (Arcoxia®, Tauxib®)ref1, ref2 : its long plasma half-life allows for once-daily oral dosing; the highest recommended daily dose for chronic use is 90 mg for rheumatoid arthritis and 60 mg for osteoarthritis and chronic low back pain. The recommended daily dose for acute pain relief treatment from primary dysmenorrhea and acute gouty arthritis is 120 mg;  same efficacy as non-COX-2 selective NSAID, with fewer gastro-intestinal adverse effects
        • deracoxib (Deramaxx®)
        • lumiracoxib (Prexige®)
    • COX-inhibiting nitric oxide-donating (CINOD)
    PGD2 synthase / PGH2 isomerase (hematopoietic)


    PGD2 synthase / PGH2 isomerase (brain)


    a-ketoreductase, family 1, member C3 / PGF2a synthase (uterus)


    microsomal PGE2 synthase (mPGES) / PGH2 isomerase


    15-hydroprostaglandin dehydrogenase


    thromboxane A2 synthase (platelets, macrophages, lung, spleen)

    dazoxiben 
    ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid) 
    ridrogrel 
    trapidil 
    BM-567 (N-pentyl-N'-[(2- cyclohexylamino-5-nitrobenzene) sulfonyl]urea) 
    picotamide (N,N'bis(3-pyridinylmethyl)-4-methoxy-isophthalamide) (Plactidil®)
    prostacycline synthase (endothelial cells, lung, spleen)


    arachidonate 5-lipoxygenase (5-LO / 5-LOX) / LTA4 synthase (nonheme iron dioxygenase; with Ca2+ and ATP translocates to the nuclear envelope from either the nuclear or cytoplasmic compartment. FLAP, a small resident nuclear envelope integral protein, acts as an apparent arachidonic acid transfer protein and facilitates presentation (WBCs : mast cell, macrophage, ...) arachidonic acid => LTA4
    zileuton (Zyflo®
    boswellic acid
    esculetin 
    5,8,11,14-eicosatetraynoic acid 
    w-3 fatty acids (OmegaBrite®, Fisol®
    • eicosapentanoic acid (EPA)
    • docosahexanoic acid (DHA)
    • octadecatetraenoic acid
    5-LOX-activating protein (FLAP)

    MK-886
    arachidonate 8-lipoxygenase (8-LOX)

    5,8,11,14-eicosatetraynoic acid
    arachidonate 12-lipoxygenase (12-LOX) (platelets, WBCs)

    5,8,11,14-eicosatetraynoic acid
    arachidonate 15-lipoxygenase (15-LOX)

    5,8,11,14-eicosatetraynoic acid
    LTA4 hydrolase (LTA4H) (a catalytic domain highly related to thermolysin and a COOH-terminal domain with armadillo-like repeats points to an interesting evolutionary heritage : because LTA4H is found in yeast, predating the appearance of other leukotriene biosynthetic enzymes, it may have had, at one time, exclusively aminopeptidase or other noneicosanoid related functions) LTA4 => LTB4
    SC57461A 
    bestatin
    LTB4 12-hydrodehydrogenase


    LTC4 synthase (a FLAP-like protein found in the nuclear envelope) LTA4 => LTC4
    MK0591
    MGST2


    MGST3


    g-glutamyl- transpeptidase (gGT) 1 (in Mus musculus g-glutamyl leukotrienase (GGLT) / g-glutamyltransferase-like activity 1) LTC4 => LTD4
    acivicin
    g-glutamyl- transpeptidase (gGT) 2


    GGTLA1


    GGTLAL1


    glutathione synthase
    glutathione S-transferase (GST) : 
    • m1 (GSTM1)
    • t1 (GSTT1)
    • p1 (GSTP1)


    buthionine-(S,R)-sulfoximine (BSO)
    neurotrasmitter anabolism indoleamine 2,3-dioxygenase (IDO) Trp
    1-methyltryptophan (1-MT)
    indoximod
    tryptophan 3-monooxygenase In mice 2 isoforms of typtophan hydroxylase-2 (Tph2), an enzyme that governs the manufacture of serotonin, exist : serotonin levels differ by 50-70% between animals with one or other of the variants 


    tyrosine hydroxylase Tyr => DOPA
    a-methyltyrosine / metyrosine (Demser®)
    aromatic L-amino acid decarboxylase (DOPA decarboxylase)
    • DOPA => DA 
    • 5-hydroxytryptophan (oxitriptan (5-HTP) (Levotonine®, Pretonine®, Serotonyl®, Triptene®) => 5-HT

    DOPA decarboxylase inhibitors (DDI)
    • carbiDOPA (Lodosyn®; in combination with L-DOPA in Atamet®, Sinemet®, Sinemet CR®) ; 
    • benserazide (+ L-DOPA = Madopar®
    • L-a-methylDOPA (competitive inhibitor)
    histidine decarboxylase His => histamine
    a-fluoromethylhistamine (irreversible inhibitor)
    histamine-N-methyltransferase (HMT) histamine
    metoprine
    neurotransmitter catabolism acetylcholinesterase (AChE) ACh => acetate + choline neurons, erythrocytes acetylcholinesterase inhibitors (AChEIs)

    onchidal
    fasciculins 
    huperzine A
    tacrine 
    1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide (BW284c51) 
    noncovalent inhibitors : 

    • edrophonium chloride (Tensilon®, Enlon®, Reversol®, ...)
    • tacrine / 1,2,3,4-tetrahydro-9-aminoacridine (Cognex®)
    • donepezil (Aricept®)
    "reversible" carbamate inhibitors 
    • eserine / physostigmine salicylate (Antilirium®) or sulfate
    • phenserine
    • neostigmine bromide or methylsulfate (Prostigmin®)
    • pyridostigmine bromide oral (Mestinon®) or parenteral (Regonol®, Mestinon®)
    • demecarium bromide (Humorsol®)
    • galantamine (Nivalin®, Razadyne®, Reminyl®)
    • rivastigmine (Exelon®, Excelon®)
    • carbamate insecticides
      • aldicarb (Temik®)
      • bendiocarb (Dycarb®, Trumpet®)
      • carbaryl (Sevin®)
      • carbofuran
      • dimetilan
      • isolan
      • methiocarb (Draza®, Bayer UK892®)
      • methomyl
      • pirimicarb (Aphox®, Pirimor®, Rapid®)
      • propoxur (Baygon®)
    organophosphorus 
    • group A, X = halogen, cyanide, or thiocyanate leaving group
      • diisopropyl fluorophosphate (DFP), isofluorophate
      • nerve gases of the G series
        • tabun (GA) / ethyl N-dimethyl phosphoramidocyanidate
        • sarin (GB) / O-isopropyl methylphosphonofluoridate
        • soman (GD) / pinacolyl methylphosphonofluoridate
        • GE
        • cyclohexyl sarin (GF)
    • group B, X = alkylthio, arylthio, alkoxy, or aryloxy leaving group
      • paraoxon / E 600 / O,O-diethyl O-(4-nitrophenyl)-phosphate (Mintacol®)
      • malaoxon / O,O-dimethyl S-(1,2-dicarboxyethyl)- phosphorothioate
      • metrifonate => dimethyl 2,2-dichlorovinyl phosphate (DDVP)
      • pirimiphos-methyl (Actellic D®, Actellic 2% dust®)
      • nerve gases of the V series
        • VE
        • VG
        • V-Gas
        • VM
        • VX / O-ethyl S-(2-diisopropyl aminoethyl) methylphosphonothiolate : absorbed through skin, 99% is degraded within 15 hours on concrete due to very high pH
    • group C, thionophosphorus or thio-thionophosphorus compounds
      • phosphorothioate insecticides
        • parathion / O,O-diethyl O-(4-nitrophenyl)- phosphorothionate (Etilon®) => paraoxon
        • methyl parathion
        • malathion / O,O-dimethyl S- (1,2-dicarbethoxyethyl) -phosphorothionate (Chemathion®, Fyfanon®, Mala-Spray®, Malathion®, Prioderm®) => malaoxon
        • diazinon / dimpylate / O,O-diethyl O-(2-isopropyl-6-methyl -4-pyridinyl)-phosphorothionate (Diazinon®, Knox-out®, Spectracide®)
        • chlorpyrifos / O,O-diethyl O-(3,5,6-trichloro-2 -pyridyl) -phosphorothionate (Dursban®, Lorsban®)
        • chlorpyrifos-methyl (Reldan 22®, Greencrop®, Storeclean®)
        • phosphamidon
        • monocrotophos
        • disulphoton phorate
      • dichlorvos (DDVP®, Vapona®, Vaponite®)
      • dithiophosphorus compounds
        • dimethoate (Cygon®, De-Fend®, Rogor®)
    • group D, pyrophosphates and similar compounds
      • tetraethyl pyrophosphate (TEPP) (Kilmite-40®, Tetron®, Vapotone®)
    • group E, quaternary ammonium compounds
      • echothiophate / MI-217 / diethoxyphosphinylthiocholine iodide (Phospholine Iodide®)
    • azinphos-methyl
    • bromophos-ethyl
    • bromophos
    • carbophenothion
    • chlorphenvinphos
    • cythioate
    • demeton-S-methyl
    • fenitrothion
    • fenthion (Lebaycid®)
    • formothion
    • heptenophos
    • jodphenphos (iodofenphos)
    • mevinphos
    • phorate
    • phosmet
    • phoxim
    reactivators 
    • hydroxylamine
    • hydroxamic acids
    • oximes
      • pyridine-2-aldoxime methyl chloride (2-PAM) / pralidoxime chloride (Protopam Chloride®)
      • pralidoxime methylsulfate (Contrathion®)
      • obidoxime (Toxogonin®)
      • HI-6
    nostocarboline
    MAO-A (in outer membranes of mitochondria of noradrenergic and dopaminergic CNS neurons, cardiomyocytes, hepatocytes, enterocytes, muscularis mucosae and muscular layers of duodenum, endothelial cells of lymphatic vessels, muscular layers and fibroblasts of arteries and veins, renal tubuli, collecting ducts and the Bowman's capsule) DA
    NE
    5-HT

    irreversible ("classical") MAO inhibitors (MAOI) (bind to FAD site) 
    • acetylenic agents / methylbenzylpropinylamine
      • clorgyline
      • pargyline (Eutonyl®, Eudatine®, Tenalin®, Paxil®, Seroxat®, Aropax®, Deroxat®)
      • rasagiline (Azilect®)
    • hydrazines
      • benmoxine (Neuralex®, Nerusil®)
      • brofaromine
      • isocarboxazide (Marplan®, Enerzer®, Marplon®
      • iproniazid (Marsilid®, Iprozid®, Ipronid®, Rivivol®, Propilniazida®)
      • iproclozide (Sursum®
      • mebanazine (Actomol®)
      • nialamide (Niamid®, Espril®, Isalizina®, Surgex®)
      • phenelzine (Nardil®, Stinerval®, Monofen®, Fenelzin®, Kalgan®, Nardelzine®)
      • pheniprazine
      • phenoxypropazine (Drazine®
    • indolalkylamine
      • etryptamine (Monase®)
    • phenylcyclopropylamine
      • tranylcypromine (Parnate®, Parmodalin®, Sicoton®, Transamin®, Transapin®, Tylciprine®)
    • pyrimidine
      • safrazine (Safra®)
    reversible inhibitors of MAO (RIMA)
    • benzamide derivatives
      • moclobemide (Aurorix®, Manerix®, Moclamine®
    • benzoxazine
      • caroxazone 
    • methylphenethylamine
      • amiflamine 
    • oxazolidinone
      • cimoxatone 
      • toloxatone (Humory, Perenum®)
    • piperidine
      • brofaromine (Consonar®)
    • pyrazino carbazole
      • pyrazidole / pirlindole 
    • pyrazino-indole tetracyclic
      • tetrindole (a tetracyclic antidepressant)
    • incazane 
    MAO-B  (in mitochondria of serotonergic neurons, cardiomyocytes, hepatocytes, enterocytes, muscularis mucosae and muscular layers of duodenum, muscular layers and fibroblasts of arteries and veins, renal tubuli, platelets) phenethylamines
    selegiline / l-deprenyl (Eldepryl®, Carbex®, Atapryl®, Lesotal®, Eldeprine®, Movergan®, Jumex®, Jumexal®, Plurimen®
    phenelzine (Nardil®, Stinerval®, Monofen®, Fenelzin®, Kalgan®, Nardelzine®
    nialamide (Niamid®, Espril®, Isalizina®, Surgex®
    tranylcypromine (Parnate®, Parmodalin®, Sicoton®, Transamin®, Transapin®, Tylciprine®)
    catechol-O- methyltransferase (COMT) L-DOPA=> 3-O-methyldopa (3-OMD)
    tolcapone (Tasmar®
    entacapone (Comtan®, Comtess®)
    GABA transaminase (GAT)

    vigabatrin / g-vinyl-GABA (Sabril®
    valproic acid / n-dipropyl acetate (Depakene®, Convulex®, Depakine®, Depalept®, Epilim®, Ergenyl®, Leptilan®, Orfiril®, Valporal®) or valproate (Depakote®, Epival®, Elvetium®, Everiden®, Novoseven®, Valcote®, Valnar®) or sodium valproate (Depacon®, Valpro®)
    succinate semialdehyde dehydrogenase (SSAD)

    valproic acid / n-dipropyl acetate (Depakene®, Convulex®, Depakine®, Depalept®, Epilim®, Ergenyl®, Leptilan®, Orfiril®, Valporal®) or valproate (Depakote®, Epival®, Elvetium®, Everiden®, Novoseven®, Valcote®, Valnar®) or sodium valproate (Depacon®, Valpro®)
    fatty acid aminohydrolase (FAAH)

    phenylmethylsulfonyl fluoride 
    methyl-arachidonoyl fluorophosphonate 
    dipeptidyl-dipeptidase (DAP) / CD10 / CALLA / neutral endopeptidase (NEP) / enkephalinase / neprilysin b-amyloid
    thiophan (N-(a-benzyl-b-thio-propionyl)glycine) 
    vasopeptidase inhibitors (VPI)
    candoxatril 
    acetorphan / racecadotril 
    LAF237 
    NN7201 
    P93/01 
    talabostat mesylate (PT-100), the amino boronic dipeptide Val-boro-Proref

    a-glucosidase
    intestinal epithelial cells acarbose (Glucobay®, Precose®
    miglitol (Glyset®)

    serine proteases (including tryptase, amylase and phospholipase A2 in pancreatic juice)

    6- (or e-) aminocaproic acid (ACA) (Amicar®
    tranexamic acid (TA) (Cyclocapron®, Cyclokapron®, Tranex®, Transamin®, Ugurol®
    aprotinin / bovine pancreatic trypsin inhibitor (BPTI)
    camostat mesilate (CM) / FOY-305 (p.o.) 
    gabexate mesilate 
    nafamostat mesilate 
    sepimostat mesilate 
    ulinastatin
    chymase 1 mast cells angiotensinogen
    angiotensin I


    prorenin / big renin => renin juxtaglomerular cells (JGC) in the walls of afferent arterioles of renal glomeruli when ... 
    • increased NaCl reapsorption in the proximal tubule (decreased pressure natriuresis) => decreased tubular delivery of Cl- to macula densa => upregulation of nNOS => peroxynitrite activates COX-2 => PGs activate JGC 
    • drop in blood pressure in afferent arteriole => stretch-activated ion channels in JGC
    • orthosympathetic system activates b1-ARs on JGC
    angiotensinogen
    synthetic tetradecapeptide renin substrate (TDP; Asp-arg-val-tyr-ile-his-pro-phe-his-leu-leu-val-tyr-ser) 

    renin binding protein (RBP)
    aliskiren / SPP100 (Rasilez®, Tekturna®
    remikiren 
    enalkiren 
    pepstratin A
    angiotensin I-converting enzyme (ACE) / kininase II / dipeptidyl carboxypeptidase / CD143 : ACE also has a GPI-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACEI and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by HPLC-MS predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activityref.
  • somatic isozyme : endothelial cells of lung capillaries
  • testis-specific isozyme : developing spermatids and mature sperm 
  • angiotensin I => angiotensin II
  • BK
  • substance P

  • ACE inhibitors (ACEI) : prodrug (drug) : -pril (-prilat) 
    • sulphydrylic ACEIs
      • alacepril (Cetapril®)
      • altiopril calcium / MC-838
      • captopril (Capoten®)
      • zofenopril (Zofenil®, Zoprace®; Zopranol®, long-lasting action)
    • carboxylic ACEIs
      • benazepril (Lotensin®) (benazeprilat) 
      • cilazapril (Inhibace®)
      • delapril hydrochloride (Adecut®)
      • enalapril (Vasotec®) (enalaprilat) (Vasotec Injection®)
      • lisinopril (Prinivil®, Zestril®; Zestoretic® in combination with hydrochlorothiazide
      • moexipril (Univasc®) (moexiprilat)
      • perindopril (Aceon®) (perindoprilat)
      • quinapril (Accupril®) (quinaprilat)
      • ramipril (Altace®, Quark®) (ramiprilat)
      • spirapril (Renomax®) (spiraprilat) 
      • trandolapril (Mavik®, Odrik®)
      • stiff lactamic
        • cilazopril (cilazoprilat)
    • phosphorylic ACEIs :
      • ceranapril
      • fosinopril sodium (Monopril®)
    • monomamide cyclomethylenic ACEIs
      • idropril
    • imidapril hydrochloride (Tanatril®)
    • temocapril hydrochloride (Acecol®
    vasopeptidase inhibitors (VPI) inhibit both ACE and neutral endopeptidase (NEP)-24.11, further reduce BK metabolism and increase vasodilator natriuretic peptides and thus may have better cardioprotective effects than ACEI : 
    • gemopatrilat 
    • omapatrilat / BMS-186716 (Vanlev®)
    • sampatrilat / UK 81252
    • fasidotril
    ACE2 renal and cardiovascular tissues (including arterial and venous endothelial cells), surface of cells in the lung, gastrointestinal system (ileum, duodenum, jejunum, caecum and colon) angiotensin I => angiotensin II


    g-glutamyl carboxylase Glu => g-carboxy-Glu / Gla (Ca2+-chelating) 

    osteocalcin
    factor II
    factor VII
    factor IX
    factor X
    GAS6
    matrix Gla protein
    protein C
    protein S
    protein Z
    PRGP1
    PRGP2
    TMG3
    TMG4


    vitamin K analogues that inhibit 2,3-epoxide reductase activity : 
    • 4-hydroxycoumarin derivatives :
      • acenocoumarol / nicoumalone (Sinthrome®, Sintron®, Sintrom®)
      • phenprocoumon (Marcumar®)
      • dicumarol / bishydroxycoumarin
      • warfarin sodium (Aldocumar®, Coumadin®, Panwarfin®, Warfilone®) : p.o., i.v.
    • indan-1,3-dione derivatives :
      • anisindione (Miradon®)
      • phenindione (Dindevan®, Pindione®)
    • rodenticides (agents of accidental or intentional poisoning)
      • bromadiolone
      • brodifacoum
      • chlorophacinone (Rogar X®)
      • diphacin
      • diphenadione
      • dicoumeral
      • fumarin
      • pindone
      • pival
      • racuman
      • ratafin
      • rodefin
      • tomorin
      • 0.25% warfarin

    prekallikrein ==factor XIIa==> kallikrein B / Fletcher factor (plasma)

    aprotinin (Trasylol®
    ecallantide / DX-88 (source : Dyax)

    kallikrein 1 (renal / pancreatic / salivary)



    kallikrein 2 (prostate)



    kallikrein 3 / PSA (prostate)



    kallikrein 4 (prostate / enamel matrix)



    kallikrein 5



    kallikrein 6



    kallikrein 7



    kallikrein 8



    kallikrein 9



    kallikrein 10



    kallikrein 11



    kallikrein 12



    kallikrein 13



    kallikrein 14



    kallikrein 15


    heme oxygenase heme oxygenase 1 (HO-1) / hsp32 (inducible) 
    curcumin (up-regulates expression) 
    caffeic acid phenethyl ester (CAPE) (up-regulates gene expression)
    Zn-(II)-protoporphyrin (ZnPP)
    heme oxygenase 2 (HO-2) (constitutive)


    heme oxygenase 3 (HO-3) (in Rattus norvegicus, constitutive)



    carbonic anhydrase I


    carbonic anhydrase II (cytoplasmic kidney)

    -zolamides : 
    • acetazolamide (Diamax®, Diamox®
    • dichlorphenamide (Daranide®
    • methazolamide (Neptazane®
    • dorzolamide hydrochloride (Trusopt®
    • brinzolamide (Azopt®)
    carbonic anhydrase III

    carbonic anhydrase IV (lumenal and basolateral membranes of pulmonary (and certain other) capillaries and of proximal renal tubules)

    carbonic anhydrase V


    carbonic anhydrase VI


    carbonic anhydrase VII


    carbonic anhydrase VIII


    carbonic anhydrase IX


    carbonic anhydrase X


    carbonic anhydrase XI


    carbonic anhydrase XII (kidney, colon, pancreas)



    thyroid peroxidase (TPo) (thyroid)

    thioureylenes / thionamides: 
    • thiouracil
    • 6-methyl-2-thiouracil
    • 6-n-propylthiouracil (PTU) (Mercazole®, Thyrozole®, Propycil®, PTU®)
    • methimazole / 1-methyl-2-mercaptoimidazole (MMI) (Tapazole®)
    • carbimazole (Neo-Mercazole®)

    type 1 5a-reductase (neutral to basic pH optimum; not detectable in the fetus, transiently expressed in newborn skin and scalp, permanently expressed in skin (sebaceous glands) from the time of puberty) testosterone => dihydrotestosterone (DHT)
    finasteride (Propecia®, Proscar®) (high doses)

    type 2 5a-reductase (transiently expressed in skin and scalp of newborns, predominant isozyme detectable in fetal genital skin, in male accessory sex organs, and in the prostate)
    finasteride (Propecia®, Proscar®) (low doses)

    3b-hydroxysteroid dehydrogenase (HSD3B) pregnenolone => progesterone
    trilostane

    11b-hydroxysteroid dehydrogenase
    • HSD11B1 [liver, brain, adipose tissue, lung, and other glucocorticoid-target tissues]
    • HSD11B2
  • inactive cortisone => active cortisol

  •  
  • active aldosterone => inactive 11-keto derivative
  • active cortisol => inactive cortisone


  • 17b-hydroxysteroid dehydrogenase



    d-aminolevulinate dehydratase

    lead (Pb)

    ferrochelatase

    lead (Pb)

    alcohol dehydrogenase (ADH) 
    • class I : homo- or heterodimers of the following subunits
    • class I : homodimer of p
    • class III : homodimer of c
    • class IV : homodimer of m/d
    • class V : homodimer of m/d
    ethanol = 100 methanol 
    4-methylpyrazole / fomepizole (Antizol®)

    aldehyde dehydrogenase (AlDH) 

    calcium carbimide (Dipsan®, Temposil®
    calcium cyanamide
    disulfiram / tetraethylthiuram disulfide (Antabuse®, Alcophobin®, Anticol®, Aversan®, Etiltoxdivalproex sodium ) : several active metabolytes of the drug, especially diethylthiomethylcarbamate 
    diethylaminobenzaldehyde (DAEB) 
    chloramphenicol

    aconitase 1 (soluble) 

    sodium fluoroacetate and fluoracetamide are incorporated into fluoroacetyl-CoA, which condenses with oxaloacetate to form fluorocitrate, the final inhibitor


    aconitase 2  (mitochondrial)



    nitric oxide synthase (NOS) NOS1 / constitutive NOS (cNOS)

  • aminoguanidine sulfate ; 
  • N-iminoethyl-L-lysine ; 
  • NG-methyl-L-arginine (L-NMMA) /  L-NG-nitrosoarginine methyl ester (L-NAME) 
  • 6-anilino-5,8-quinolinequinone / LY83583 / LY 
  • asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of NOS. ADMA inhibits vascular NO production in concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intraarterially. Thus, elevated ADMA levels may explain the "L-arginine paradox," i.e., the observation that supplementation with exogenous L-arginine improves NO-mediated vascular functions in vivo, although its baseline plasma concentration is about 25-fold higher than the Michaelis-Menten constant Km of the isolated, purified endothelial NO synthase in vitro. The biochemical and physiological pathways related to ADMA are well understood: dimethylarginines are the result of degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, symmetric dimethylarginine, are eliminated from the body by renal excretion, whereas only ADMA is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. Plasma ADMA levels are increased in humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic interventions. Among other potential strategies that are currently being tested, administration of L-arginine has been shown to improve endothelium-dependent vascular functions in subjects with high ADMA levels. Finally, ADMA has gained clinical importance recently because several studies have shown that ADMA is an independent cardiovascular risk factorref
  • L-NNA 
  • methylene blue
  • NOS2 / inducible NOS (iNOS)


    NOS3 / endothelial NOS (eNOS)



    arginase 1

    Nw-hydroxy-L-arginine 
    Nw-hydroxy-nor-L-arginine
    suppressor of cytokine signaling (SOCS) / cytokine-induced STAT inhibitor (CIS) / STAT-induced STAT inhibitor (SSI) family (SH2 domain and SOCS box) SOCS1
    SOCS2
    SOCS3
    SOCS4 / SOCS6
    SOCS5
    SOCS7
    CIS




    thioredoxin

    MOL 294
    superoxide dismutase (SOD) SOD1 (soluble, CuZn)

    triethylenetetramine (TETA) 
    KCN
    SOD2 (mitochondrial, Mn)


    SOD3 (in Mus musculus, extracellular, CuZn)


    Bcl-2 family antiapoptotic members(group I) : BH4-BH3-BH2-BH1 -TM (~ CED9 in Caenorhabditis elegans pro-apoptotic members (~ egl-1 in Caenorhabditis elegans

    obatoclax mesylate (GX15-070), a small molecule pan–Bcl-2 family antagonist
    ABT-199 (Bcl-2-selective)
    oteins containing His residues


    diethylpyrocarbonate
    proteins containing Cys residues


    iodoacetamide


    family (identity > 40%)
    subfamily (identity > 55%)
    isoform






    CYP1A1 (up-regulated by AHR) aromatic compounds




    CYP1A2 aromatic compounds 
    flutamide





    CYP1B1 dioxin




    CYP2A phenobarbital




    CYP2A6 tegafur




    CYP2A7





    CYP2A13





    CYP2B





    CYP2B6 (up-regulated by VDR) cyclophosphamide

    orphenadrine 


    CYP2B7





    CYP2C (Rattus norvegicus) mephenytoin
    paclitaxel





    CYP2C8 mephenytoin




    CYP2C9 : 3 SNPs (up-regulated by VDR) mephenytoin
    warfarin
    phenytoin
    sulfonylureas





    CYP2C18 mephenytoin




    CYP2C19 : 8 SNPs mephenytoin
    PPIs





    CYP2D4 (in Mus musculus only)





    CYP2D5 (in Mus musculus only)





    CYP2D6 (in Homo sapiens only) (not inducible !) : ~ 70 SNPs 
    • poor metabolizers (PM)
    • intemediate metabolizers (IM)
    • extensive metabolizers (EM)
    • ultrarapid metabolizers (UM)
    ~ 65 drugs (most abandoned nowadays due to SNPs) : 
    debrisoquine 
    sparteine 
    codeine
    methadone
    tyramine 
    tryptamine 
    paroxetine
    fluoxetine
    tamoxifen


    quinidine
    SSRIs


    CYP2E1 (in both Homo sapiens and Mus musculus) ethanol
    acetaminophen => N-acetyl-p-benzoquinoneimine 
    benzene
    phenol 
    chlorophorm
    lungs



    CYP2F1





    CYP2G1





    CYP2G2





    CYP2J2 arachidonic acid




    CYP2S1





    CYP3A niphedipine
    cyclosporine A
    tacrolimus


    troleandomycin


    CYP3A4 (up-regulated by VDR) 60% of clinically prescribed drugs :  enterocytes, hepatocytes, kidney
    troleandomycin


    CYP3A5 niphedipine




    CYP3A7 niphedipine




    CYP3A43





    CYP4A1 (Mus musculus)





    CYP4A3(Mus musculus)





    CYP4A11





    CYP4B1





    CYP4F2 / LTB4 w-hydrolase  => 20-hydroxy-PGs




    CYP4F3 / LTB4 w-hydrolase  => 20-hydroxy-PGs




    CYP4F8  => 19R-hydroxyPGs




    CYP4F11





    CYP4F12





    CYP4X1





    CYP7A1 (rate-limiting enzyme in the neutral bile acid biosynthetic pathway)





    CYP7B1





    CYP8B1 / sterol 12a-hydroxylase





    CYP11A1 / cholesterol 20,22-desmolase / cholesterol side-chain-cleaving enzyme (P450scc) cholesterol

    aminoglutethimide (Cytadren©
    ketoconazole (Nizoral®) (at low doses)


    CYP11B1 / 11b-hydroxylase


    ketoconazole (Nizoral®
    metyrapone (Metopirone®)


    CYP11B2 / steroid 11b hydroxylase / 18-hydroxylase


    ketoconazole (Nizoral®)


    CYP17A1 / steroid 17a-hydroxylase / 17,20 lyase


    ketoconazole (Nizoral®) (at low doses) 
    CB7630 / abiraterone acetate


    CYP19 / aromatase androstenedione 
    testosterone
    16 a-hydroxyandrostenedione


    aromatase inhibitors (A) : 
    • aminoglutethimide (Cytadren©, Orimeten®
    • dexaminoglutethimide 
    • YM-511 
    • MK0434
    • finrozole / MPV-2213ad (source : Hormos Medical Ltd., Turku, Finland) 
    • steroidal androstenedione analogs :
      • formestane (Lentaron®)
      • exemestane (Aromasin®)
    • imidazole or nonsteroidal structure (NSS)-AI :
      • anastrozole (Arimidex®)
      • fadrozole / CGS 16949 A (Afema®)
      • letrozole (Femara®; source : Novartis) : used in 13 cases as a fertility treatment because it suppresses estrogen and can promote ovulation, it is actually teratogenic and cause miscarriages and should be used only in postmenopausal women with breast cancer
      • vorozole


    CYP21A2 / steroid 21-hydroxylase





    CYP24 / steroid 24-hydroxylase (up-regulated by VDR)
  • 1a,25-(OH)2-vitamin D3 => 1a,24R,25-(OH)3-vitamin D3
  • 25-(OH)-vitamin D3 => 24R,25-(OH)2-vitamin D3
  • inner mitochondrial membrane of proximal convoluted renal tubule cells



    CYP26A1 all-trans retinoic acid




    CYP27A1 / steroid 25-hydroxylase vitamin D3=> 25-(OH)-vitamin D3 hepatocytes
    HIV-protease inhibitors


    CYP27B1 / steroid 1a-hydroxylase (down-regulated by VDR) 25-OH-vitamin D3 => 1a,25-(OH)2-vitamin D3 inner mitochondrial membrane of proximal convoluted renal tubule cells, activated macrophages, activated astrocytes, keratinocytes, placenta
    HIV-protease inhibitors


    CYP39A1





    CYP46 / cholesterol 24-hydroxylase





    CYP51A1 / steroid 14a-demethylase


    ketoconazole (Nizoral®)


    NAT1





    NAT2 : 15 SNPs isoniazid
    procainamide
    dapsone
    hydralazine
    caffeine





    dihydropyrimidine dehydrogenase (DPYD) 5-FU




    thiopurine S-methyltransferase (TPMT) 6-MP




    epoxide hydrolase 1


    valproic acid


    TGM1 / K polypeptide epidermal type I, protein-glutamine-g-glutamyltransferase





    TGM2 / C polypeptide, protein-glutamine-g-glutamyltransferase


    immunodominant gluten peptide in which Gln has been replaced with a 6-diazo-5-oxo-Nle residue


    TGM3 / E polypeptide, protein-glutamine-g-glutamyltransferase





    TGM3-like





    TGM4 prostate




    TGM5





    TGM6 / coagulation factor XIII





    TGM7 / transglutaminase Z




    aminopeptidases aminopeptidase N / CD13


    competitive inhibitors : 
    • ubenimex
    • actinonin

    leucine aminopeptidase (LAP3)


    bestatin 
    CHR-2797 / tosedostat (source : Chroma Therapeutics Ltd; orally bioavailable) is a novel metalloenzyme inhibitor that is converted into a pharmacologically active acid product (CHR-79888) inside cellsref

    placental leucine aminopeptidase




    adipocyte-derived leucine aminopeptidase / ERAP1





    methionine aminopeptidase-1 (MetAP-1)





    methionine aminopeptidase-2 (MetAP-2)


  • replacement of the C4 side chain by benzyloxime preserves the inhibitory activity against MetAP-2 enzyme
    • fumagillin
    • ovalicin
    • bestatin-type
      • A-357300
    • O-(chloracetyl-carbamoyl) fumagillol / TNP-470 /AGM-1470, an analogue of fumagillin toxic to proliferative endothelial cells : a water-soluble conjugate of biocompatible N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470 prevents it crossing the blood–brain barrier (BBB), and also leads to its selective accumulation in tumour vessels because of the enhanced permeability and retention (EPR) effect, thereby minimizing weight loss and neurotoxicityref

    • FK866/K22.175 (FK-866), developed as an anticancer agent, interferes with the NAD+ biosynthesis and  a strong antiangiogenic potencyref

     

    ATP-binding cassette (ABC) proteins : the human's 49 known ABC genes are beat out by fly, worm and mouse (56, 56, and 51 respectively), and are dwarfed by the 129 known Arabidopsis thaliana genes.
    ABCA1 (monomeric) liver, intestine, placenta, adipose, and spleen



    ABCA2




    ABCA3




    ABCA4




    ABCA5




    ABCA6




    ABCA7




    ABCA8




    ABCA9




    ABCA10




    ABCA11




    ABCA12




    ABCA13




    ABCB1/ P-glycoprotein (P-GP) / MDR1 / GP170
  • lumenal surface of brain capillaries (blood-brain barrier (BBB))
  • neurons
  • testes
  • proximal renal tubular cells
  • enterocytes
  • pancreas
  • bronchial mucosa
  • hepatocytes
  • placenta
  • low expression on blood cells, gonads, and breast
  • amphipathic, lipid soluble : 
    first-generation agents :  second-generation agents : 
    • biricodar dictrate (Incel®)
    • valspodar / PSC 833 (Amdray®)
    third-generation inhibitors : 
    • laniquidar / R101933
    • ONT-093
    • tariquidar / XR9576
    • zosuquidar trihydrochloride / LY335979
     

    ABCB2 / TAP1




    ABCB3 / TAP2




    ABCB4




    ABCB5




    ABCB6 highly expressed in human fetal liverref
  • iron
  • porphyrin 



  • ABCB7
    heme from mitochondria to cytosol


    ABCB8




    ABCB9




    ABCB10




    ABCB11 / bile salt efflux pump (BSEP)
    bile salts across hepatocyte canalicular mebrane into bile


    ABCC1 / MDR-associated protein type 1 (MRP1)
  • oxidized glutatione
  • cysteinyl leukotrienes
  • activated aflatoxin B1

  • glucuronides and sulfate conjugates of steroid hormones and bile salts



    ABCC2 / MDR-associated protein type 2 (MRP2)
  • brush border of proximal renal tubule
  • hepatocytes

  • apical membrane of enterocytes
    amphipathic anions and conjugated metabolites 
    • vinblastine
    • glucuronides
    • sulfates
    • glutathione adducts



    ABCC3 / MDR-associated protein 3 (MRP3)




    ABCC4 / MDR-associated protein 4 (MRP4) brain tumor cells topotecan


    ABCC5 / MDR-associated protein 5 (MRP5)




    ABCC6 / MDR-associated protein 6 (MRP6)




    ABCC7 / CFTR is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing of the pore have been linked to ATP binding and hydrolysis at CFTR's 2 nucleotide-binding domains, NBD1 and NBD2)ref
    Cl-
    HCO3- + Cl-

    2-thioxo-4-thiazolidinones : 
    • CFTRinh-172 (Ki = 300 nM)
    glyburide / glibenclamide (Micronase®, Diabeta®, Euglucan®, Glynase®; Glucovance® in combination with metformin
    niflumic acid (NFA) (Niflam®
    diphenylamine-2-carboxylate

    ABCC8 / MDR-associated protein 8 (MRP8) / sulfonylurea receptor 1 (SUR1) (associated to KCNJ11)ref b cells of pancreatic Langerhans' isletsref
    a endosulfine
    b endosulfine
    sulfonylureas : 
    • first-generation analogs
      • tolbutamide (Orinase®)
      • chlorpropamide (Diabinese®; Chlorformin® in combination with phenformin)
      • tolazamide (Tolinase®)
      • acetohexamide (Dymelor®)
    • second-generation analogs
      • glyburide / glibenclamide (Micronase®, Diabeta®, Euglucan®, Glynase®; Glucovance® in combination with metformin)
      • glipizide (Glucotrol®)
      • gliclazide (Diamicron®, ...)
        • immediate release (IR)
        • modified reease (MR)
      • glimepiride (Amaryl®)
    meglitinide analogues : 
    • repaglinide (Prandin®
    • nateglinide (Starlix®)
    • mitiglinide / KAD-1229


    ABCC9 / sulfonylurea receptor 2 (SUR2)ref cardiac, skeletal, and vascular and non-vascular smooth muscle
    sulfonylureas: 
    • first-generation analogs
      • tolbutamide (Orinase®)
      • chlorpropamide (Diabinese®)
      • tolazamide (Tolinase®)
      • acetohexamide (Dymelor®)
    • second-generation analogs
      • glyburide / glibenclamide (Micronase®, Diabeta®, Glynase®; Glucovance® in combination with metformin)
      • glipizide (Glucotrol®)
      • gliclazide (Diamicron®, ...)
        • immediate release (IR)
        • modified reease (MR)
      • glimepiride (Amaryl®)
    meglitinide analogues 
    • repaglinide (Prandin®
    • nateglinide (Starlix®)
    • mitiglinide / KAD-1229


    ABCC10 / MDR-associated protein 7 (MRP7)




    ABCC11 / MDR-associated protein 8 (MRP8)




    ABCC12 / MDR-associated protein 9 (MRP9)




    ABCC13




    ABCD1




    ABCD2




    ABCD3




    ABCD4




    ABCE1




    ABCF1




    ABCF2




    ABCF3




    ABCG1 (dimeric) macrophages



    ABCG2 / BRCP cancer cells  mitoxantrone (sequestered into extracellular vesiclesref)
    Ko143 
    fumitremorgin C 
    imatinib

    ABCG3




    ABCG4 (dimeric) macrophages



    ABCG5 / sterolin-1 (dimeric) liver and small intestine (apical sterol export pumps that promote active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion) sterolins / phytosterols


    ABCG8 / sterolin-2 (dimeric)

















    ATP1A1 : ATPase, Na+/K+ transporting, alpha 1 polypeptide





    ATP1A2 ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide





    ATP1A3 ATPase, Na+/K+ transporting, alpha 3 polypeptide





    ATP1A4 ATPase, Na+/K+ transporting, alpha 4 polypeptide





    ATP1B1 ATPase, Na+/K+ transporting, beta 1 polypeptide





     ATP1B2 ATPase, Na+/K+ transporting, beta 2 polypeptide





     ATP1B3 ATPase, Na+/K+ transporting, beta 3 polypeptide





     ATP1B4 ATPase, (Na+)/K+ transporting, beta 4 polypeptide




    sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) ATP2A1 / SERCA1
    cardiac muscle, fast twitch 1
    thapsigargin
    L12ADT


    ATP2A2 / SERCA2 (2 isoforms : SERCA2a and SERCA2b) 
    cardiac muscle, slow twitch 2
    thapsigargin
    L12ADT


    ATP2A3 / SERCA3
    ubiquitous
    thapsigargin
    L12ADT


     ATP3 ATPase, Mg++ transporting





    ATP4A ATPase, H+/K+ exchanging, alpha polypeptide





    ATP4B ATPase, H+/K+ exchanging, beta polypeptide





    ATP5A1 ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit, isoform 1, cardiac muscle





    ATP5A2 ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit, isoform 2, non-cardiac muscle





    ATP5B ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide





    ATP5C1 ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 1





    ATP5C2 ATP synthase, H+ transporting, mitochondrial F1 complex, gamma polypeptide 2





    ATP5D ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit





    ATP5E ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit





    ATP5F1 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit b, isoform 1





    ATP5G1 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit c (subunit 9), isoform 1 





     ATP5G2 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit c (subunit 9), isoform 2





     ATP5G3 ATP synthase, H+ transporting, mitochondrial F0 complex, subunit c (subunit 9) isoform 3





     ATP5H ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d





     ATP5I ATP synthase, H+ transporting, mitochondrial F0 complex, subunit e





     ATP5J ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6





     ATP5L ATP synthase, H+ transporting, mitochondrial F0 complex, subunit g 





    MTATP6 ATP synthase 6





    ATP7A ATPase, Cu+ transporting, a polypeptide (Menkes syndrome)





    ATP7B ATPase, Cu+ transporting, b polypeptide (Wilson disease)





    MTATP8 ATP synthase 8





    ATP9A ATPase, Class II, type 9A





    ATP9B ATPase, Class II, type 9B 





    ATP10A ATPase, Class V, type 10A 





    ATP10B ATPase, Class V, type 10B 





    ATP10D ATPase, Class V, type 10D 





    ATPAF1 ATP synthase mitochondrial F1 complex assembly factor 1 





    ATPAF2 ATP synthase mitochondrial F1 complex assembly factor 2





     










































    farnesyl diphosphate synthase (farnesyl pyrophosphate synthetase, dimethylallyltranstransferase, geranyltranstransferase)


    bisphosphonates are pyrophosphate analogs : 
    • first-generation, nonnitrogen-containing bisphosphonates have antiresorptive activity at dose levels from 0.1 to 10 mg P/kg. Some first generation analogues are now used to treat metabolic bone disease but, when given orally, their efficacy in aggressive resorptive disease may be limited because of low potency
      • clodronate (Bonefos®)
      • etidronate sodium / ethylenehydroxydiphosphonate (Didrocal®, Didronel®)
    • aminobisphosphonates / nitrogen-containing bisphosphonates (N-BPs)
      • second generation amino-bisphosphonates characterized by an amino terminal group and a higher antiresorptive potency (in growing rats ranges from 0.01 to 1 mg P/kg.)
        • alendronate (Fosamax®; Merck and Company, Inc.; West Point, PA) p.o.
        • pamidronate / aminohydroxypropane diphosphonate (Aredia®; Novartis Pharmaceuticals Corp.; East Hanover, NJ) i.v.
      • third generation bisphosphonates are characterized by a cyclic chain, was synthesized. It includes series of pyridinyl ethane bisphosphonates, pyridinyl aminomethane bisphosphonates, indan bisphosphonates, cyclopentane bisphosphonates, piperidyl ethane bisphosphonates, pyridinyl and piperidyl hydroxyethane bisphosphonates, piperidinylidene aminomethane bisphosphonates, and pyridinyl oxa- and thiomethane bisphosphonates. Several of these show antiresorptive activity in growing rats as low as 0.001 mg P/kg
        • ibandronate (Bondronat®, Bonvival®; Hoffmann-La Roche Inc.; Nutley, NJ) i.v.
        • risedronate (Actonel®; Actonel with Calcium® in combination with calcium carbonate; Proctor and Gamble Pharmaceuticals, Inc.; Cincinnati, OH) p.o.
        • zoledronate (Zometa®; Novartis Pharmaceuticals Corp.) i.v.
    • medronate / methylene diphosphonate
    • minodronate (YM529)
    • neridronate
    • olpadronate
    • oxidronate / hydroxymethylene diphosphonate
    • tiludronate (Skelid®)


    farnesyl-diphosphate farnesyltransferase 1 (FDFT1) farnesyl pyrophosphate 

    farnesyl transferase inhibitors (FTI) : synthetic FTIs have been designed based on the structures of 2 substrates that are involved in the reaction, FPP and Ras CAAX tetrapeptide. Ras-competitive inhibitors that have been synthesized, both CAAX-related and CAAX-unrelated, display nanomolar inhibitory potency toward FTase but retain selectivity against GGTase-I 
    • p.o.
      • lonafarnib / SCH66336 (Sarasar®)

      • tipifarnib / R115777 (Zarnestra®)

    • i.v. : BMS-214662
    • J-104,871ref










    poly(ADP-ribose) polymerase (PARP)


    PJ34 (phenanthridinone-based) 
    INO-1001 
    3-aminobenzamide (ABA) 
    3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2h)-isoquinolinone 
    olaparib (AZD2281) 


    thiamine pyrophosphokinase
    thiamine => TPP / TDP
    neopyrithiamine / pyrithiamine 
    oxythiamine


    pyridoxal kinase
    pyridoxal => pyridoxal phosphate
    isonicotinic acid hydrazone
    calmodulins
    calmodulin 1
    calmodulin 2
    calmodulin 3
    calmodulin-like 1
    calmodulin-like 3



    zaldaride


    glyceraldehyde-3-phosphate dehydrogenase (GAPDH)


    koningic acid (KA)


    telomerase reverse transcriptase (TERT)


    catalytic inhibitors 
    antisense phosphorothioate (AS-ONS) for telomerase template 
    • GRN163 (a 13-mer N3'-->P5' thio-phosphoramidate (NPS) oligonucleotide)
    folding of the DNA substrate 
    inhibitors of the HSP90 chaperone function : 
    • geldanamycin (GA)
    • 17-allylamino,17-demethoxygeldanamycin (17-AAG)
    AZT / zidovudine
    lamivudine
    3-(3,5-dichlorophenoxy)-nitrostyrene (DPNS) 
    2,3,7-trichloro-5-nitroquinoxaline (TNQX) 
    dictyodendrins A-E (1-5) 
    2,3-dibromosuccinato [2-(methylaminomethyl)pyridine]platinum (II) (compound E) 
    epigallocatechin gallate (EGCG) and synthetic derivatives : 
    • SR13193
    • SR13196
    gossypol
    MST-312 
    MST-295 
    MST-1991 
    arabinofuranosylguanine 5'-triphosphate (araGTP) 
    3'-azido-2',3'-dideoxyguanosine 5'-triphosphate (AZdGTP) 
    2',3'-dideoxy-2'-fluoroarabino-furanosylguanine 5'-triphosphate (FaraGTP) 
    quadruplex telomeric G-rich ssDNA 
    • telomestatin (SOT-095)


    matrix metalloproteinases (MMP) : multidomain zinc endopeptidases with a metzincin-like catalytic domain MMP1 / interstitial collagenase



    batimastat / BB-94 (hydroxamate peptidomimetic ) 
    ilomastat / galardin / GM 6001 
    marimastat / BB 2516 / TA 2516 (orally bioavailable analogue ) 
    SC 44463 
    o-phenanthroline 
    collagen peptidomimetics 
    nonpeptidomimetic inhibitors of the MMP active site 
    tetracycline derivatives competing for Zn :  bisphosphonates
    MMP2 / gelatinase A / 72 kDa type IV collagenase



    MMP3 / stromelysin 1 / progelatinase



    MMP7 / uterine matrilysin



    MMP8 / neutrophil collagenase



    MMP9 / gelatinase B / 92 kDa type IV collagenase



    MMP10 / stromelysin 2



    MMP11 / stromelysin 3



    MMP12 / macrophage elastase



    MMP13 / collagenase 3



    MMP14 / MT1-MMP / membrane inserted (an activator of MMP-2)



    MMP15 / membrane inserted



    MMP16 / membrane inserted



    MMP17 / membrane inserted



    MMP18 / MMP19



    MMP20 / enamelysin



    MMP21



    MMP23A



    MMP23B / MMP22



    MMP24 / membrane inserted



    MMP25



    MMP26



    MMP27



    MMP28



    calpain




    MDL 28170 
    cholesteryl ester transfer protein, plasma (CETP)
    hepatocytes


    JTT-705 
    torcetrapib / CP-529414 
    anacetrapib / MK-0859
    lipase, gastric




    orlistat / tetrahydrolipstatin (THL) (Xenical®
    ATL-962
    lipase, pancreatic




    orlistat / tetrahydrolipstatin (THL) (Xenical®
    ATL-962
    HMG-CoA reductase HMG-CoA hepatocytes


    -statins / HMGRIs  : 
    • atorvastatin (Lipitor®, Totalip®)
    • cerivastatin (Baycol®, Stativa®, Cervasta®)
    • fluvastatin (Lescol®)
    • lovastatin / mevilonin (prodrug) (Mevacor®)
    • mevastatin / compactinref
    • pitavastatin / NK-104 (Livalo®)
    • pravastatin (Pravachol®)
    • rosuvastatin / ZD4522 (Crestor®, Simestat®)
    • simvastatin (prodrug) (Zocor®; Vytorin® or Inegy® in combination with ezetimibe)
    microsomal triglyceride transfer protein (MTP)




    lomitapide / AEGR-773 / BMS-201038 (Juxtapid®)
    acylCoA:cholesterol acyltransferase 1 (ACAT-1) cholesterol, acylCoA macrophage


    avasimibe / CI-1011
    acylCoA:cholesterol acyltransferase 2 (ACAT-2) cholesterol enterocytes and hepatocytes



    Pim kinases Pim-1



    SGI-1776
    Pim-2




    Pim-3




    lipoprotein lipase (LPL)
    adipocytes, skeletal muscle cells, and macrophages (including foamy cells in atherosclerotic lesions, where it can bind and retain LDLs in subendothelial space)



    hepatic triglyceride lipase (HTGL)
    hepatocytes



    phospholipid transfer protein (PLTP)
    liver and lungs



    lecithin:cholesterol acyl transferase (LCAT)
    hepatocytes



    squalene synthase / farnesyl-diphosphate farnesyl transferase 1 farnesyl pyrophosphate 



    squalestatin 1ref
    zaragosic acids A, B, and C (fungal metabolites)ref
    1,1-bisphosphonate esters : 
    • SR-45023A (ApomineTM) ?ref

    • SR-12813ref
    ER-27856  5-{N-[2-butenyl-3-(2-methoxyphenyl)]-N-methylamino}-1,1-penthylidenebis(phosphonic acid) trisodium saltref

    RPR 107393 {3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride} and its R and S enantiomers (p.o.; also inducer of HMG-CoA reductase, resulting in the accumulation of metabolites of FPP. After the administration of radiolabeled mevalonate, hepatic levels of labeled dicarboxylic acids in RPR 107393-treated rats were shown in the present study, raising the possibility of toxicity with this treatment. It is known, however, that dicarboxylic acids derived from geraniol are readily excreted in urine, so rapid urinary excretion as the dicarboxylic acids may be the fate of the accumulated mevalonate after RPR 107393 treatmentref
    some bisphosphonatesref1, ref2
    GTP cyclohydrolase I (GTPCH)




    2,4-diamino-6-hydroxypyrimidine
    N-acetyl-L-aspartyl-L-glutamate (NAAG) peptidase / glutamate carboxypeptidase II (GCPII) N-acetyl-aspartyl-glutamate (NAAG)



  • 2-(phosphonomethyl) pentanedioic acid (2-PMPA) 
  • ZJ-43
  • HIF-1a prolyl 4-hydroxylase (HPH)





    dipeptidyl peptidase 4 (DPP-4) GLP-1
    CXCL12




  • sitagliptin phosphate / MK-0431 (Januvia®; JanuMet® in combination with metformin)
  • vildagliptin / LAF-237 (Galvus®)
  • saxagliptin / BMS-477118 (Onglyza®)
  • Syk




    R788 (fostamatinib disodium), an oral prodrug that is rapidly converted to a potent and relatively selective inhibitor of Syk (R406)ref
    ALK




    crizotinib / PF-02341066 (Pfizer)
    Aurora kinasesref Aurora A kinase



    MLN8504 (Aurora-A IC50 = 0.034 µmol/L; Aurora-B IC50 = 5.7 µmol/L)
    Aurora B kinase



    indolinone 
    • quinazoline derivatives :
      • hesperadin (Boeheringer Ingelheim)
    • 4,6-diaminopyrimidine :
      • ZM447439
      • AZD1152-HQPA (Aurora B-selective)
    • tetrahydropyrrolo[3,4-c]pyrazole derivative :
      • PHA-739358
    MK-0457 / VX680 (source: Vertex => Merck) 
    AT9283 (source : Astex therapeutics) 
    AS703569 
    ZM447439 (source : AstraZeneca) (both Aurora-A and Aurora-B with an IC50 of ~100 nmol/L)
    Compound 677 (source : AstraZeneca) (Aurora B-selective)
    Aurora C kinase




    GTP-binding proteins, or GTPasesref, are proteins that cycle back and forth between 2 conformations that determine their activity: in the first conformation, they are bound by a GTP cofactor that activates them biochemically; whereas, in the second conformation, they are GDP-bound and inactive. GTPases have hydrolysis activity that catalyses the conversion of the GTP moiety to GDP or GMP (GDP in the case of the p47 GTPases). The level of hydrolysis activity varies for particular GTPases, and it canbe modulated by other cellular factors, such as GTPase-activating factors, such as GTPase-activting proteins (GAPs). Once the protein is in the GDP-bound/inactive state, a cellular guanine exchange factor (GEF) catalyses the replacement of GDP with GTP, which reactivates the protein. So, the activity of GTPases is regulted by functions that are inherent to the protein as well as by accessory proteins. The fraction of the GTPase that is in the active state varies widely according to the particular GTPase, and according to the cellular environment. For example, the small GTPase RAS is about 7% GTP-bound in queiescent fibroblasts, but becomes more active and 22% is GTP-bound in fibroblasts that have been transformed by the v-src and v-abl virusesref. By contrast, most of the p47 GTPases in cells seem to be in a GTP-bound state, and are therefore active. At the primary sequence level, GTPases have 3 conserved amino-acid motifs- Gly-Xaa-Xaa-Xaa-Xaa-Gly-Lys(Ser/Thr), Asp-Xaa-Xaa-Gly and Asn-Lys-Xaa-Asp - that bind the guanine nucleotide and a Mg2+ cofactorref. In addition, some GTPases are membrane bound, with a covalently attached lipid chain such as myristoyl or prenyl group that medites association with the membraneref. Once in the GTP-bound state, GTPases effect their functions, which range from activation of cell surface receptors to modulation of membrane-fusion events. Although the precise cellular function of the p47 GTPases is unknown, GTP binding triggers the formation of oligomeric complexes.

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