ENZYMES
2011; Wiley; Volume: 164; Issue: s1 Linguagem: Inglês
10.1111/j.1476-5381.2011.01649_9.x
ISSN1476-5381
AutoresSPH Alexander, A Mathie, JA Peters,
ResumoEnzymes are protein catalysts facilitating the conversion of substrates into products. The Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (NC-IUBMB) classifies enzymes into families, using a four number code, on the basis of the reactions they catalyse. There are six main families: EC 1.-.-.- Oxidoreductases; EC 2.-.-.- Transferases; EC 3.-.-.- Hydrolases; EC 4.-.-.- Lyases; EC 5.-.-.- Isomerases; EC 6.-.-.- Ligases. Many enzymes require additional entities for functional activity. Some of these are used in the catalytic steps, while others promote a particular conformational change. Co-factors are tightly bound to the enzyme and include metal ions and heme groups. Co-enymes are typically small molecules which accept or donate functional groups to assist in the enzymatic reaction. Examples include ATP, NAD, NADP and S-adenosylmethionine, as well as a number of vitamins, such as riboflavin (vitamin B1) and thiamine (vitamin B2). The majority of drugs which act on enzymes act as inhibitors; one exception is metformin, which appears to stimulate activity of AMP-activated protein kinase, albeit through an imprecisely-defined mechanism. Kinetic assays allow discrimination of competitive, non-competititve and un-competitive inhibitors. The majority of inhibitors are competitive (acting at the enzyme's ligand recognition site), non-competitive (acting at a distinct site; potentially interfering with co-factor or co-enzyme binding) or of mixed type. One rare example of an uncompetitive inhibitor is lithium ions, which are effective inhibitors at inositol monophosphatase only in the presence of high substrate concentrations. Some inhibitors are irreversible, including a group known as suicide substrates, which bind to the ligand recognition site and then couple covalently to the enzyme. Although there are many more enzymes than receptors in biology, and many drugs that target prokaryotic enzymes are effective medicines, overall the number of enzyme drug targets is relatively small (Overington et al., 2006), which is not to say that they are of modest importance. Overington JP, Al-Lazikani B, Hopkins AL (2006). How many drug targets are there? Nat Rev Drug Discovery5: 993–996. http://www.chem.qmul.ac.uk/iubmb/ Overview: Adenosine is a multifunctional, ubiquitous molecule that acts at cell-surface G protein-coupled receptors, as well as numerous enzymes, including protein kinases and adenylyl cyclase. Extracellular adenosine is thought to be produced either by export or by metabolism, predominantly through ecto-5′-nucleotidase activity (also producing inorganic phosphate). It is inactivated either by extracellular metabolism via adenosine deaminase (also producing ammonia) or, following uptake by nucleoside transporters, via adenosine deaminase or adenosine kinase (requiring ATP as co-substrate). Intracellular adenosine may be produced by cytosolic 5′-nucleotidases or through S-adenosylhomocysteine hydrolase (also producing homocysteine). An extracellular adenosine deaminase activity, termed ADA2 or adenosine deaminase growth factor (ADGF, CECR1, ENSG00000093072) has been identified (see Maier et al., 2005), which is insensitive to EHNA (Zavialov et al., 2010). Other forms of adenosine deaminase act on ribonucleic acids and may be divided into two families: ADAT1 (ENSG00000065457) deaminates transfer RNA; ADAR (EC 3.5.4.-, ENSG00000160710, also known as 136 kDa double-stranded RNA-binding protein, P136, K88DSRBP, Interferon-inducible protein 4); ADARB1 (EC 3.5.-.-, ENSG00000197381, also known as dsRNA adenosine deaminase) and ADARB2 (EC 3.5.-.- , ENSG00000185736, also known as dsRNA adenosine deaminase B2, RNA-dependent adenosine deaminase 3) act on double-stranded RNA. Particular polymorphisms of the ADA gene result in loss-of-function and severe combined immunodeficiency syndrome. Adenosine deaminase is able to complex with dipeptidyl peptidase IV (EC 3.4.14.5, ENSG00000197635, also known as T-cell activation antigen CD26, TP103, adenosine deaminase complexing protein 2) to form a cell-surface activity (Kameoka et al., 1993). Abbreviations: 5′-AMP, adenosine 5′-monophosphate; 5′NT, 5′-nucleotidase; A134974, N7-[(1′r,2′s,3′r,4′s)-2′,3′-dihydroxy-4′-aminocyclopentyl]-4-amino-5-iodopyrrolopyrimidine; ABT702, 4-amino-5-(3-bromophenyl)-7-(6-morpholinopyridin-3-yl)pyrido[2,3-d]pyrimidine; ADA, adenosine deaminase; ADK, adenosine kinase, EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride; Aiuti A, Cattaneo F, Galimberti S et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med360: 447–458. Blackburn MR, Kellems RE (2005). Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol86: 1–41. Boison D (2006). Adenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci27: 652–658. Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R et al. (2001). Adenosine deaminase: functional implications and different classes of inhibitors. Med Res Rev21: 105–128. Hershfield MS (2005). New insights into adenosine-receptor-mediated immunosuppression and the role of adenosine in causing the immunodeficiency associated with adenosine deaminase deficiency. Eur J Immunol35: 25–30. Hunsucker SA, Mitchell BS, Spychala J (2005). The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther107: 1–30. Kloor D, Osswald H (2004). S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Trends Pharmacol Sci25: 294–297. Maier SA, Galellis JR, McDermid HE (2005). Phylogenetic analysis reveals a novel protein family closely related to adenosine deaminase. J Mol Evol61: 776–794. Overview: The amino acid hydroxylases (monooxygenases) are iron-containing enzymes which utilise molecular oxygen and tetrahydrobiopterin as co-substrate and co-factor, respectively. Abbreviations: DOPA, 3,4-dihydroxyphenylalanine; PCPA, 4-chlorophenylalanine Daubner SC, Le T, Wang S (2011). Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys508: 1–12. Lehmann IT, Bobrovskaya L, Gordon SL, Dunkley PR, Dickson PW (2006). Differential regulation of the human tyrosine hydroxylase isoforms via hierarchical phosphorylation. J Biol Chem281: 17644–17651. Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M (2010). Tryptophan hydroxylase as novel target for the treatment of depressive disorders. Pharmacology85: 95–109. Waider J, Araragi N, Gutknecht L, Lesch KP (2011). Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. Psychoneuroendocrinology36: 393–405. Zhang X, Beaulieu JM, Gainetdinov RR, Caron MG (2006). Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2. Cell Mol Life Sci63: 6–11. Overview: L-arginine is a basic amino acid with a guanidino sidechain. As an amino acid, metabolism of L-arginine to form L-ornithine, catalysed by arginase, forms the last step of the urea production cycle. L-Ornithine may be utilised as a precursor of polyamines (see Carboxylases and Decarboxylases, Page S286) or recycled via L-arginosuccinate to L-arginine. L-Arginine may itself be decarboxylated (see Page S286) to form agmatine, although the prominence of this pathway in human tissues is uncertain. L-Arginine may be used as a precursor for guanidinoacetate formation in the creatine synthesis pathway under the influence of arginine:glycine amidinotransferase with L-ornithine as a byproduct. Nitric oxide synthase uses L-arginine to generate nitric oxide, with L-citrulline also as a byproduct. L-Arginine in proteins may be subject to post-translational modification through methylation, catalysed by protein arginine methyltransferases. Subsequent proteolysis can liberate asymmetric NG,NG-dimethyl-L-arginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase activities. ADMA is hydrolysed by dimethylarginine dimethylhydrolase activities to generate L-citrulline and dimethylamine. Arginase (EC 3.5.3.1) are manganese-containing isoforms, which appear to show differential distribution, where the ARG1 isoform predominates in the liver and erythrocytes, while ARG2 is associated more with the kidney. N ω-Hydroxyarginine, an intermediate in NOS metabolism of L-arginine acts as a weak inhibitor and may function as a physiological regulator of arginase activity. Although isoform-selective inhibitors of arginase are not available, examples of inhibitors selective for arginase compared to NOS are Nω-hydroxy-nor-L-arginine (Tenu et al., 1999), S-(2-boronoethyl)-L-cysteine (Colleluori and Ash, 2001; Kim et al., 2001) and 2(S)-amino-6-boronohexanoic acid (Baggio et al., 1999; Colleluori and Ash, 2001). Arginine:glycine amidinotransferase (AGAT, E.C. 2.1.4.1) Dimethylarginine dimethylaminohydrolases (DDAH, EC 3.5.3.18) are cytoplasmic enzymes which hydrolyse NG,NG-dimethyl-L-arginine to form dimethylamine and L-citrulline. Nitric oxide synthases (NOS, E.C. 1.14.13.39) utilise L-arginine (not D-arginine) and molecular oxygen to generate nitric oxide and L-citrulline. The nomenclature suggested by NC-IUPHAR of NOS I, II and III (see Moncada et al., 1997) has not gained wide acceptance. eNOS and nNOS isoforms are activated at concentrations of calcium greater than 100 nM, while iNOS shows higher affinity for Ca2+/calmodulin and thus appears to be constitutively active. All the three isoforms are homodimers and require tetrahydrobiopterin, flavin adenine dinucleotide, flavin mononucleotide and NADPH for catalytic activity. L-NAME is an inhibitor of all three isoforms, with an IC50 value in the micromolar range. The reductase domain of NOS catalyses the reduction of cytochrome c and other redox-active dyes (Mayer and Hemmens, 1997). NADPH:O2 oxidoreductase catalyses the formation of superoxide anion/H2O2 in the absence of arginine and tetrahydrobiopterin. Protein arginine N-methyltransferases (PRMT, EC 2.1.1.-) encompass histone arginine N-methyltransferases (PRMT4, PRMT7, EC 2.1.1.125) and myelin basic protein N-methyltransferases (PRMT7, EC 2.1.1.126). They are dimeric or tetrameric enzymes which use S-adenosyl-L-methionine as a methyl donor, generating S-adenosyl-L-homocysteine as a by-product. They generate both mono-methylated and di-methylated products; these may be symmetric (SDMA) or asymmetric (ADMA) versions, where both guanidine nitrogens are monomethylated or one of the two is dimethylated, respectively. A related gene has been described, CARM1L (Coactivator associated arginine methyltransferase 1-like fragment, ENSG00000227835). Abbreviations: 1400W, N-(3-(aminomethyl) benzyl)acetamidine; ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; NADPH, reduced nicotinamide adenosine dinucleotide phosphate; 7NI, 7-nitroindazole; NIL, L-N6-(1-iminoethyl)lysine; NOS, nitric oxide synthase; PIBTU, 13-phenylen-bis(1,2-ethanediyl)bis-thiourea; PRMT, protein arginine methyltransferase; SDMA, symmetric dimethylarginine Bedford MT, Clarke SG (2009). Protein arginine methylation in mammals: who, what, and why. Mol Cell33: 1–13. Heemskerk S, Masereeuw R, Russel FG, Pickkers P (2009). Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. Nat Rev Nephrol5: 629–640. Huang PL (2009). eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab20: 295–302. Krause CD, Yang ZH, Kim YS, Lee JH, Cook JR, Pestka S (2007). Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol Ther113: 50–87. Kukreja RC, Xi L (2007). eNOS phosphorylation: a pivotal molecular switch in vasodilation and cardioprotection? J Mol Cell Cardiol42: 280–282. Leiper J, Nandi M (2011). The therapeutic potential of targeting endogenous inhibitors of nitric oxide synthesis. Nat Rev Drug Discov10: 277–291. Lundberg JO, Weitzberg E (2010). NO-synthase independent NO generation in mammals. Biochem Biophys Res Commun396: 39–45. Maarsingh H, Pera T, Meurs H (2008). Arginase and pulmonary diseases. Naunyn Schmiedebergs Arch Pharmacol378: 171–184. Maarsingh H, Zaagsma J, Meurs H (2009). Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. Br J Pharmacol158: 652–664. Melikian N, Seddon MD, Casadei B, Chowienczyk PJ, Shah AM (2009). Neuronal nitric oxide synthase and human vascular regulation. Trends Cardiovasc Med19: 256–262. Moncada S, Higgs A, Furchgott R (1997). International Union of Pharmacology Nomenclature in Nitric Oxide Research. Pharmacol Rev49: 137–142. Morris SM Jr. (2009). Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol157: 922–930. Mount PF, Kemp BE, Power DA (2007). Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. J Mol Cell Cardiol42: 271–279. Munder M (2009). Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol158: 638–651. Palm F, Onozato ML, Luo Z, Wilcox CS (2007). Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol293: H3227–H3245. Teyssier C, Le Romancer M, Sentis S, Jalaguier S, Corbo L, Cavailles V (2010). Protein arginine methylation in estrogen signaling and estrogen-related cancers. Trends Endocrinol Metab21: 181–189. Toda N, Ayajiki K, Okamura T (2009). Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev61: 62–97. Tousoulis D, Boger RH, Antoniades C, Siasos G, Stefanadi E, Stefanadis C (2007). Mechanisms of disease: L-arginine in coronary atherosclerosis–a clinical perspective. Nat Clin Pract Cardiovasc Med4: 274–283. Tsutsui M, Shimokawa H, Otsuji Y, Yanagihara N (2010). Pathophysiological relevance of NO signaling in the cardiovascular system: novel insight from mice lacking all NO synthases. Pharmacol Ther128: 499–508. Carboxylases: The carboxylases allow the production of new carbon-carbon bonds by introducing HCO3- or CO2 into target molecules. Two groups of carboxylase activities, some of which are bidirectional, can be defined on the basis of the cofactor requirement, making use of biotin (EC 6.4.1.-) or vitamin K (EC 4.1.1.-). Citrate and other dicarboxylic acids are able to activate ACC1/ACC2 activity allosterically. PCC is able to function in forward and reverse modes as a ligase (carboxylase) or lyase (decarboxylase) activity, respectively. Loss-of-function mutations in GGCX are associated with clotting disorders. Decarboxylases: The decarboxylases generate CO2 and the indicated products from acidic substrates, requiring pyridoxal phosphate (ADC, AADC, GAD, HDC, ODC and PSDC) or pyruvate (SAMDC and PSDC) as a co-factor. The presence of a functional ADC activity in human tissues has been questioned (Coleman et al., 2004). s-Allylglycine is also an inhibitor of SAMDC (Pajunen et al., 1979). The activity of ODC is regulated by the presence of an antizyme (ENSF00000002504) and an ODC antizyme inhibitor (ENSF00000002504). Abbreviations: AMA, S-(5′-deoxy-5′-adenosyl)-methylthioethyl-hydroxylamine; APA, 1-aminooxy-3-aminopropane; DFMO, α-difluoromethyl-L-ornithine, also known as eflornithine; FMH, α-fluoromethylhistidine; SAM, S-adenosylmethionine; SAM486A, 1-guanidinoimino-2,3-dihydroindene-4-carboximidamide, also known as CGP48664; TOFA, 5-(tetradecyloxy)-2-furancarboxylic acid Akbarian S, Huang HS (2006). Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders. Brain Res Rev52: 293–304. Bale S, Ealick SE (2010). Structural biology of S-adenosylmethionine decarboxylase. Amino Acids38: 451–460. Brownsey RW, Boone AN, Elliott JE, Kulpa JE, Lee WM (2006). Regulation of acetyl-CoA carboxylase. Biochem Soc Trans34: 223–227. Elmets CA, Athar M (2010). Targeting ornithine decarboxylase for the prevention of nonmelanoma skin cancer in humans. Cancer Prev Res (Phila)3: 8–11. Jitrapakdee S, St MM, Rayment I, Cleland WW, Wallace JC, Attwood PV (2008). Structure, mechanism and regulation of pyruvate carboxylase. Biochem J413: 369–387. Jitrapakdee S, Vidal-Puig A, Wallace JC (2006). Anaplerotic roles of pyruvate carboxylase in mammalian tissues. Cell Mol Life Sci63: 843–854. Marin-Valencia I, Roe CR, Pascual JM (2010). Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab101: 9–17. Moya-Garcia AA, Pino-Angeles A, Gil-Redondo R, Morreale A, Sanchez-Jimenez F (2009). Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition. Br J Pharmacol157: 4–13. Pegg AE (2006). Regulation of ornithine decarboxylase. J Biol Chem281: 14529–14532. Pegg AE (2009). S-Adenosylmethionine decarboxylase. Essays Biochem46: 25–45. Saggerson D (2008). Malonyl-CoA, a key signaling molecule in mammalian cells. Annu Rev Nutr28: 253–272. Smith KJ, Skelton H (2006). α-Difluoromethylornithine, a polyamine inhibitor: its potential role in controlling hair growth and in cancer treatment and chemo-prevention. Int J Dermatol45: 337–344. Tong L, Harwood HJ Jr. (2006). Acetyl-coenzyme A carboxylases: versatile targets for drug discovery. J Cell Biochem99: 1476–1488. Wolfgang MJ, Lane MD (2006). The role of hypothalamic malonyl-CoA in energy homeostasis. J Biol Chem281: 37265–37269. Overview: cyclic nucleotides are second messengers generated by cyclase enzymes from precursor triphosphates and hydrolysed by phosphodiesterases. The cellular actions of these cyclic nucleotides are mediated through activation of protein kinases (cAMP- and cGMP-dependent protein kinases, see page S310), ion channels (cyclic nucleotide-gated, CNG, and hyperpolarization and cyclic nucleotide-gated, HCN, see Pages S153 & S156) and guanine nucleotide exchange factors (GEFs, Epac). Overview: Adenylyl cyclase (ENSF00000000188) converts 5′-ATP to 3′,5′-adenosine monophosphate and pyrophosphate. Mammalian membrane-bound adenylyl cyclases are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators forskolin, NKH477 (except AC9, Premont et al., 1996) and Gαs (the stimulatory G protein α subunit, see Page S5). Adenosine and its derivatives (e.g. 2′,5′-dideoxyadenosine), acting through the P-site, appear to be physiological inhibitors of adenylyl cyclase activity (Tesmer et al., 2000). Three families of adenylyl cyclase are distinguishable: Ca2+/CaM-stimulated (AC1, AC3 and AC8), Ca2+-inhibitable (AC5 and AC6) and Ca2+-insensitive (AC2, AC4 and AC7) forms. Nitric oxide has been proposed to inhibit AC5 and AC6 selectively (Hill et al., 2000), although it is unclear whether this phenomenon is of physiological significance. A soluble adenylyl cyclase has been described (ENSG00000143199, Buck et al., 1999), unaffected by either Gα or Gβγ subunits, which has been suggested to be a cytoplasmic bicarbonate (pH-insensitive) sensor (Chen et al., 2000). Overview: Soluble guanylyl cyclase (GTP diphosphate-lyase (cyclising)) is a heterodimer comprising α and β chains, both of which have two subtypes in man (predominantly α1β1; see Zabel et al., 1998). A haem group is associated with the β chain and is the target for the endogenous ligand nitric oxide (NO•), and, potentially, carbon monoxide (Friebe et al., 1996). The enzyme converts guanosine-5′-triphosphate (GTP) to the intracellular second messenger 3′,5′-guanosine monophosphate (cGMP). ODQ also shows activity at other haem-containing proteins (Feelisch et al., 1999), while YC1 may also inhibit cGMP-hydrolysing phosphodiesterases (Friebe et al. 1998; Galle et al., 1999). Overview: Epacs are members of a family of guanine nucleotide exchange factors (ENSFM00250000000899), which also includes RapGEF5 (GFR, KIAA0277, MR-GEF, ENSG00000136237) and RapGEFL1 (Link-GEFII, ENSG00000108352). They are activated endogenously by cyclic AMP and with some pharmacological selectivity by 8-pCPT-2′-O-Me-cAMP (Enserink et al., 2002). Once activated, Epacs induce an enhanced activity of the monomeric G proteins, Rap1 and Rap2 by facilitating binding of GTP in place of GDP, leading to activation of phospholipase C (Schmidt et al., 2001) (see Page S302). Overview: 3′,5′-Cyclic nucleotide phosphodiesterases (PDEs, 3′,5′-cyclic-nucleotide 5′-nucleotidohydrolase) catalyse the hydrolysis of a 3′,5′-cyclic nucleotide (usually cyclic AMP or cyclic GMP). IBMX is a nonselective inhibitor with an IC50 value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2′,3′-cyclic nucleotide 3′-phosphodiesterase (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS. PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane-bound homodimer. EHNA is also an inhibitor of adenosine deaminase (E.C. 3.5.4.4) (see Page S280). PDE3A and PDE3B are membrane-bound. PDE4 isoforms are essentially cAMP specific. The potency of YM976 at other members of the PDE4 family has not been reported. PDE4B–D long forms are inhibited by extracellular signal-regulated kinase (ERK)-mediated phosphorylation (Hoffmann et al., 1998; Hoffmann et al., 1999). PDE4A–D splice variants can be membrane-bound or cytosolic (Houslay and Adams, 2003). PDE4 isoforms may be labelled with [3H]-rolipram. PDE7A appears to be membrane-bound or soluble for PDE7A1 and 7A2 splice variants, respectively. BRL50481 appears not to have been examined as an inhibitor of PDE7B. PDE6 is a membrane-bound tetramer composed of two catalytic chains (PDE6A or PDE6C and PDE6B), an inhibitory chain (PDE6G or PDE6H) and the PDE6D chain. The enzyme is essentially cGMP specific and is activated by the α-subunit of transducin (Gαt, see Page S5) and inhibited by sildenafil, zaprinast and dipyridamole with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness. Abbreviations: BAY412272, 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine); BAY607550, 2-(3,4-dimethoxybenzyl)-7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl}-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one; BRL50481, 5-nitro-2,N,N-trimethylbenzenesulfonamide; CaM, calmodulin; EHNA, erythro-9-(2-hydroxy-3-nonyl)adenine; NKH477, 6-(3-dimethylaminopropionyl) forskolin hydrochloride; NKY80, 2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone; ODQ, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; PKA, protein kinase A or cyclic AMP-dependent protein kinase; PKC, protein kinase C; PKG, protein kinase G or cyclic GMP-dependent protein kinase; RGS2, Regulator of G-protein signalling 2 (ENSG00000116741); Ro201724, 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone; SCH51866, cis-5,6a,7,8,9,9a-hexahydro-2-(4-[trifluoromethyl]phenylmethyl)-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one; YC1, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole; YM976, (4-[3-chlorophenyl]-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one); Borland G, Smith BO, Yarwood SJ (2009). EPAC proteins transduce diverse cellular actions of cAMP. Br J Pharmacol158: 70–86. Cerra MC, Pellegrino D (2007). Cardiovascular cGMP-generating systems in physiological and pathological conditions. Curr Med Chem14: 585–599. Cheng X, Ji Z, Tsalkova T, Mei F (2008). Epac and PKA: a tale of two intracellular cAMP receptors. Acta Biochim Biophys Sin (Shanghai)40: 651–662. Feldman RD, Gros R (2007). New insights into the regulation of cAMP synthesis beyond GPCR/G protein activation: implications in cardiovascular regulation. Life Sci81: 267–271. Gloerich M, Bos JL (2010). Epac: defining a new mechanism for cAMP action. Annu Rev Pharmacol Toxicol50: 355–375. Grandoch M, Roscioni SS, Schmidt M (2010). The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. Br J Pharmacol159: 265–284. Holz GG, Chepurny OG, Schwede F (2008). Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors. Cell Signal20: 10–20. Jackson EB, Mukhopadhyay S, Tulis DA (2007). Pharmacologic modulators of soluble guanylate cyclase/cyclic guanosine monophosphate in the vascular system – from bench top to bedside. Curr Vasc Pharmacol5: 1–14. Metrich M, Berthouze M, Morel E, Crozatier B, Gomez AM, Lezoualc'h F (2010). Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology. Pflugers Arch459: 535–546. Roscioni SS, Elzinga CRS, Schmidt M (2008). Epac: effectors and biological functions. Naunyn-Schmiedebergs Arch Pharmacol377: 345–357. Schmidt M, Sand C, Jakobs KH, Michel MC, Oude Weernink PA (2007). Epac and the cardiovascular system. Curr Opin Pharmacol7: 193–200. Willoughby D, Cooper DMF (2007). Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev87: 965–1010. Overview: the cytochrome P450 enzyme family (CYP450) were originally defined by their strong absorbance at 450 nm due to the reduced carbon monoxide-complexed haem component of the cytochromes. They are an extensive family of haem-containing monooxygenases with a huge range of both endogenous and exogenous substrates. Listed below are the human enzymes; their relationship with rodent CYP450 enzyme activities is obscure in that the species orthologue may not mediate metabolism of the same substrates. Although the majority of CYP450 enzyme activities are concentrated in the liver, the extrahepatic enzyme activities also contribute to patho/physiological processes. Genetic variation of CYP450 isoforms is widespread and likely underlies a significant proportion of the individual variation to drug administration. CYP2A7P1 (ENSG00000213908), CYP2D7P1 (ENSG00000205702), CYP2G1P (ENSG00000130612) and AC008537.5-2 (ENSG00000198251, fragment) are uncharacterized potential pseudogenes from the same families. AC004597.1 (ENSG00000225607) is described as being highly similar to CYP4F12. Cipollone F, Cicolini G, Bucci M (2008). Cyclooxygenase and prostaglandin synthases in atherosclerosis: recent insights and future perspectives. Pharmacol Ther118: 161–180. Fleming I (2008). Vascular cytochrome P450 enzymes: physiology and pathophysiology. Trends Cardiovasc Med18: 20–25. Haining RL, Nichols-Haining M (2007). Cytochrome P450-catalyzed pathways in human brain: metabolism meets pharmacology or old drugs with new mechanism of action? Pharmacol Ther113: 537–545. Hisaka A, Ohno Y, Yamamoto T, Suzuki H (2010). Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther125: 230–248. Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007). Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther116: 496–526. Johnson WW (2008). Cytochrome P450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance. Drug Metab Rev40: 101–147. Johnston JB, Ouellet H, Podust LM, Ortiz de Montellano PR (2011). Structural control of cytochrome P450-catalyzed ω-hydroxylation. Arch Biochem Biophys507: 86–94. Kirchheiner J, Seeringer A (2007). Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta1770: 489–494. Laursen T, Jensen K, Moller BL (2011). Conformational changes of the NADPH-dependent cytochrome P450 reductase in the course of electron transfer to cytochromes P450. Biochim Biophys Acta1814: 132–138. Omura T (2010). Structural diversity of cytochrome P450 enzyme system. J Biochem147: 297–306. Ortiz de Montellano PR (2010). Hydrocarbon hydroxylation by cytochrome P450 enzymes. Chem Rev110: 932–948. Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H (2008). Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol82: 667–715. Rezen T, Contreras JA, Rozman D (2007). Functional genomics approaches to studies of the cytochrome P450 superfamily. Drug Metab Rev39: 389–399. Schuster I (2011). Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta1814: 186–199. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W (2010). P450 enzymes: their structure, reactivity, and selectivity-modeled by QM/MM calculations. Chem Rev110: 949–1017. Wijnen PA, Op den Buijsch RA, Drent M, Kuijpers PM, Neef C, Bast A, Bekers O, Koek GH (2007). The prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment Pharmacol Ther26 (Suppl. 2): 211–219. Zanger UM, Turpeinen M, Klein K, Schwab M (2008). Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem392: 1093–1108. Eicosanoids are 20-carbon fatty acids, where the usual focus is the polyunsaturated analogue arachidonic acid and it's metabolites. Arachidonic acid is thought primarily to derive from phospholipase A2 action on membrane phosphatidylcholine (see Page S302), and may be re-cycled to form phospholipid through conjugation with coenzyme A and subsequently glycerol derivatives. Oxidative metabolism of arachidonic acid is conducted through three major enzymatic routes: cyclooxygenases; lipoxygenases and cytochrome P450-like epoxygenases, particularly CYP2J2 (see Page S293). Isoprostanes are structural analogues of the prostanoids (hence the nomenclature D-, E-, F-isoprostanes and isothromboxanes), which are produced in the presence of elevated free radicals in a non-enzymatic manner, leading to suggestions for their use as biomarkers of oxidative stress. Molecular targets for their action have yet to be defined. Overview: Prostaglandin (PG) G/H synthase, most commonly referred to as cyclooxygenase (COX, (5Z,8Z,11Z,14Z)-icosa-
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