Reductases and Dehydrogenases N- Acetyl and S- Methyl Transferases
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1 MEDCH527 1/26/2015 Reductases and Dehydrogenases - Acetyl and S- Methyl Transferases Collec2vely, these enzymes account for ~10% of metabolic reac2ons (Testa et al., Drug Discovery Today, 2012)
2 Reduc9on in Drug Metabolism Reduc2ve drug metabolism is one of the least studied and, from an enzymological perspec2ve, the most poorly characterized of the common drug metabolism processes. Testa s treatment of the biochemistry of metabolic reduc2on in Chem. Biodivers. Vol 4 (2007) is an invaluable guide to this complicated subject. Reduc2on of carbonyls (aldehydes, ketones, quinones) is the most common metabolic reduc2on that drugs, other xenobio2cs and endogenous compounds undergo. Vitamin K CH 3 Phytyl H CH 3 H Vitamin KH 2 Phytyl
3 Major Enzymes Catalyzing Carbonyl Reduc9on (Adapted from Testa, 2007) and P450 reductase (CPR)!
4 CPR CPR CPR Testa (2007) Reduc9on
5 Hydride transfer mechanism for carbonyl reduc2on
6 Cofactors for Carbonyl Reduc2on Despite their molecular diversity, and the fact that some, but not all, catalyzes reversible reac2ons, these enzymes are united by their use of ADH and/or ADPH cofactors (see below). Alcohol dehydrogenases (ADH) Aldo- keto reductases (AKR) - aldehyde/aldose reductases (AR) - hydroxysteroid dehydrogenases (HSD) - many dihydrodiol dehydrogenases /(DHD) Carbonyl reductases (CR) Quinone oxidoreductase (Q) P450 reductase (CPR) Zn- containing, ADH- dependent ADPH- dependent ADPH- dependent ADPH- dependent ADPH- dependent
7 Quinone Reduc2on by Q1 and CPR H + 1 e + 1 e (+ 2H + ) H Quinone Semiquinone radical anion Hydroquinone Microsomal ADPH- dependent cytochrome P450 reductase (CPR, PR) catalyzes the one- electron reduc2on of quinones to a reac2ve semiquinone radical intermediate. ADPH- dependent quinone oxidoreductase (Q1; DT- Diaphorase) is an FAD- containing, cytosolic enzyme with an exquisite sensi2vity towards the inhibitor, dicoumarol; Ki = 1 nm. Q1 catalyzes the obligatory two electron reduc2on of quinones, and so bypasses the semiquinone radical.
8 Quinone toxicity: RS genera9on and protein aryla9on Quinones may react directly with thiols on proteins to cause toxicity Quinones can react with molecular oxygen to form RS Q1- catalyzed two- electron reduc2on to the hydroquinone is a more benign process, since it bypasses the semiquinone radical
9 Importantance of Quinones to Drug Toxicity [Testa et al., 2012; =473 toxicity reac2ons]
10 Reduc2ve bioac2va2on of an2cancer pro- drugs CPR- catalyzed one electron reduc2on forms radicals, which in normal cells react with oxygen to forms superoxide anion that can be detoxified by SD. In solid tumors that are low in oxygen because of poor neo- vasculariza2on radicals persist and can cause DA strand breaks in tumor cells. Q- catalyzed reduc2on to the E09 hydroquinone ac2vates the azaridinyl ring for nucleophilic afack by DA. Q1 is upregulated in many cancers. CH 2 H R Q X (+) H CH 2 H R CH 3 H CH 3
11 Azo- and itro- reduc2on These reac2ons are typically catalyzed by intes2nal microflora in the anerobic environment of the lower GIT. However, under condi2ons of low oxygen tension, P450, Q1 and aldehyde oxidase may also contribute.
12 Reduc2ve dehalogena2on and toxicity Reduc2ve dehalogena2on of CCl4 and the anesthe2c halothane generates carbon- centered radicals that ini2ate lipid peroxida9on. Downstream toxic metabolites include C and phosgene. xida1ve dehalogena2on of halothane generates trifuuoroacetaldehyde that causes immune hepa99s following neo- an2gen forma2on.
13 - Acetyl transferases (AT) ATs (AT1 and AT2) catalyze the transfer of an acetyl group from the cofactor, acetyl- CoA, mainly to rela2vely lipophilic compounds that contain a primary amino group. X- ray crystal structures of prokaryo2c AT enzymes from S. typhimurium and M. smegma1s have been solved demonstra2ng 3 domains. The first two - terminal domains are highly conserved in ATs throughout both the eukaryo2c and prokaryo2c kingdoms, and contain an ac2ve site cataly9c triad composed of Cys69- His107- Asp122 (numbering scheme from S. typhimurium). -Acetyltransferase (AT) CoA S C CH 3 AT C Cys CH 3 R H C CH 3 RH 2 AT
14 - Acetyltransferase Reac9ons - acetyla2on is a major route of biotransforma2on for xenobio2cs containing a primary arylamine (R- H 2 ) or a hydrazine group (R- H- H 2 ). Products are aroma2c amides (R- H- CCH 3 ) and hydrazides (R- H- H- CCH 3 ), respec2vely. C 2 H S H H H 2 H 2 H 2 PABA Sulfamethazine Procainamide H H 2 H H 2 H H 2 Hydralazine Isoniazid Phenelzine H 2 H 2 H 2 Benzidine 2-Aminofluorene
15 - Acetyltransferase Reac9ons (cont d) Xenobio2cs containing primary alipha2c amines are rarely substrates for - acetyla2on. The important excep2on being cysteine conjugates, which are formed from glutathione conjugates and converted to mercapturic acids by - acetyla2on in the kidney (see Atkins lecture on GSH). Some drugs are metabolized to primary amines before acetyla2on. H H S H 2 H Sulfasalazine itrazepam
16 ATs: The Enzymes - acetyla2on is carried out in mammals by AT 1 and AT2, cytosolic enzymes of M.W. ~ kda. AT1 and AT2 share 87% nucleo2de and 81% amino acid sequence iden22es. Human ATs are encoded at 3 separate loci on chromosome 8. ne of the loci contains a non- expressed pseudogene AT3. AT ac2vity has been found in most organisms and all mammals, where there is high ac2vity in the liver. There is ~50% overall sequence homology for all ATs with a conserved ac2ve site cysteine required for cataly2c ac2vity as the acetyla2on site.
17 AT1 is ubiquitously expressed. It catalyzes the acetyla2on of monomorphic substrates, such as sulfamethoxazole and p- aminosalisylic acid. AT2 is expressed primarily in the liver and intes2nal mucosa and catalyzes the acetyla2on of what has been termed polymorphic substrates, including sulfamethazine, isoniazid, dapsone, sulfamethoxazole, procainamide, hydralazine and caffeine..
18 AT slow acetylators AT polymorphism first iden2fied as the slow acetylator phenotype in pa2ents using the hydrazine drug, isoniazid ~50% of pa2ents were observed to suffer ADRs, i.e. hepatotoxicity and peripheral neuropathy Slow acetylator frequencies: 55-60% in Caucasians /orthern Europeans 8-10% Japanese, 20% Chinese 90% orth Africans Slow acetylator status due largely to polymorphisms in AT2
19 AT2 Polymorphisms: Caffeine Acetylator Status Phenotyped in urine by the ra2o of AFMU:1- methylxanthine
20 AT2- dependent slow acetyla9on AT2*4 is wild- type, responsible for most fast acetylator ac2vity Slow acetylator phenotype due largely to AT2*5, AT2*6, AT2*7, AT2*14 alleles Low ac2vity due to: Poor expression/unstable protein (AT2*5) Decreased cataly2c ac2vity (AT2*6) Some studies have demonstrated a much greater frequency of homozygous slow acetylators (91%) in Caucasian children with documented skin allergies, than in disease- free children (62%). Sensi2za2on may be mediated by increased forma2on of hydroxylamines, e.g. seen with sulfonamides. Epidemiological studies on the role of AT polymorphisms in cancer suscep2bility and sulfonamide toxicity are quite confusing with oven contradictory findings.
21 Role of ATs in aroma9c amine genotoxicity SULT R S 3 H S 3 H R Reac%ve nitrenium ion; DA binding
22 SAM and Methyltransferases SAM - ature s methyl iodide serves as the methyl group donor for S- methyltransferase (e.g. TPMT), - methyl transferase (e.g. CMT) and - methyltransferase enzymes. R-X-H R-X-CH 3 H 2 C 2 H CH CH 2 CH 2 H 2 C 2 H CH CH 2 CH 2 S H 3 C CH 2 adenosine S CH 2 adenosine S-adenosyl methionine (SAM) S-adenosyl homocysteine Methyltransferase reac2ons differ from other conjuga2ons in that they typically decrease the water solubility of the resul2ng metabolites.
23 S-, - and - Methyl Transferases Main func2onal groups involved: Thiols (TPMT/TMT) Catechols (CMT) Aroma2c and alipha2c amines (MT) Mostly endogenous substrates, but some drugs are metabolized by these enzymes: Captopril (TMT) 6- Mercaptopurine (TPMT) L- DPA, Methyldopa (CMT) ico2ne (MT)
24 S- Methyltransferases: Enzymes and Substrates At least two dis2nct enzymes (TMT and TPMT) each of which requires SAM. Thiol methyl transferase (TMT) is a microsomal enzyme that catalyzes the methyla2on of alipha2c thiols, e.g. captopril. CH 3 CH 3 H 2 C SH H 2 C S CH 3 Thiopurine methyl transferase (TPMT) is a 28 kda cytosolic enzyme that catalyzes the methyla2on of aroma2c and heteroaroma2c substrates 2 H 3 C S H SH H S CH 3 H Azathioprine 6-Mercaptopurine 6-Thiomethyl mercaptopurine
25 6- Mercaptopurine Disposi9on (Purine salvage) Bioac1va1on Pathway 6- MP HGPRT TIMP (mul2ple enzyma2c steps) TG DA TPMT TPMT Detoxifica1on Pathway TPMT MeMP X 6- TU MTMP ther products TPMT: thiopurine methyltransferase X: xanthine oxidase HGPRT: hypoxanthine guanine phosphoribosyltransferase TIMP: 6- thioinosine monophosphate MTMP: 6- S- methylthioinosine monophosphate TG: 6- thioguanine nucleo2des 6- MP: 6- mercaptopurine MeMP: 6- S- methylmercaptopurine 6- TU: 6- thiouric acid
26 6- MP Dose Adjustment Based on TPMT Genotype Common alleles confer reduced enzyme stability Strategy is to focus on the most common defec2ve alleles and adjust 6- MP dose downward for ~10% of pa2ents. Krynetski and Evans, Pharmacology 61:136-46, 2000
27 CMT Cytosolic (liver and kidney) and membrane- bound forms (brain) ~25 kda enzymes requiring magnesium CMT inhibitors e.g. entacapone, used in Parkinsonism Metabolizes neurotransmifers, catechol estrogens and drugs that undergo metabolism to catechols. Methyla2on occurs at the meta posi2on. CH 3 H CH 3 H CH 3 HCH 3 H HCH 3 H 3 C HCH 3
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