Catechol 3-methyltransferase structure

Taskinen J, Ethell BT, Pihlavisto P, Hood AM, Burchell B, Coughtrie MW. Conjugation of catechols by recombinant human sulfotransferases, UDP-glucuronosyltransferases, and soluble catechol O-methyltransferase structure-conjugation relationships and predictive models. Drug Metab Dispos 2003 31 1187-97. 

Catechol-O-Methyltransferase. Figure 3 Chemical structures of some inhibitors of catechol O-methylation. 

Structural Aspects in the Inhibitor Design of Catechol O-Methyltransferase... 

Tenhunen J, Salminen M, Jalanko A, Ukkonen S, Ulmanen I. Structure of the rat catechol-O-methyltransferase gene separate promoters are used to produce mRNAs for soluble and membrane-bound forms of the enzyme. DNA and Cell Biology 1993 12 253-263. 

VIDGREN, J., SVENSSON, L.A., LILJAS, A., Crystal structure of catechol O-methyltransferase, Nature, 1994,368, 354-357. 

McIntosh AM, Baig BJ, Hall J, Job D, Whalley HC, et al. 2007. Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis. Biol Psychiatry 61 1127-1134. 

The enzyme catechol-O-methyltransferase (COMT) is involved in pain regulation and regulation of neurotransmitters. COMT acts to catalyze the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM, 5) to the 0 of catecholate 4 (Reaction 9.5). The catechol structure is found in neurotransmitters such as dopamine, noradrenahne, and adrenaline. A related set of enzymes are the DNA methyltransferases that appear to have similar structure, especially in their active sites, to the structure of COMT. ... 

Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS. Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites Structure-activity relationship and molecular-modeling studies. Biochem Pharmacol 2005 69 1523-31. 

Rutherford K, Daggett V (2009) A hotspot of inactivation the A22S and V108M polymorphisms individually destabilize the active site structure of catechol O-methyltransferase. 

Rutherford K, Le Trong I, Stenkamp RE, Person VW (2008) Crystal structures of human 108V and 108M catechol O-methyltransferase. J Mol Biol 380 120... 

An extremely interesting application of KIEs and theory has been elucidating the effect of enzyme catalysis on the structure of the SN2 transition state. Schowen and coworkers29 30 measured the secondary a-deuterium and a-carbon 12C/13C KIEs for the enzyme-catalyzed SN2 methyl transfer reaction between G-adenosylmethionine (Fig. 18) and 3,4-dihydroxyacetophenone in the presence of the rat-liver enzyme catechol O-methyltransferase (COMT) at 37°C (Fig. 19) and for the closely related, uncatalyzed Sn2 reaction between methoxide ion and G-methyldibenzothiophenium ion in methanol at 25°C (Fig. 20). The near maximum a-carbon KIEs of 1.09 + 0.02 for the enzyme-catalyzed SN2 reaction and 1.08 + 0.01 for the uncatalyzed Sn2 reaction were taken as evidence that both transition states were symmetric. However,... 

MT family of enzymes catalyzes the O-, S-, or N-methylation of drugs, hormones, and neurotransmitters, and utilizes S-adenosyl-L-methionine (SAM) as a methyl donor. Catechol-O-methyltransferase (COMT) is the most extensively investigated drug-metabolizing MT. It plays an important role in the biotransformation of both endogenous and exogenous catechols. COMT has a rather broad substrate specificity for structures that contain catechol moieties and is often involved in the methylation of... 

Alkaloids which inhibit acetylcholine esterase, monoamine oxidase and catechol-O-methyltransferase are tabulated in Table 11. Potent ACE blocker are indole alkaloids of the physostigmine type (e.g., eseramine, geneserine, physovenine, eserine), protoberberine alkaloids (e.g., berberine, columbamine, coptisine, jatrorrhizine, palmatine), steroidal alkaloids (leptine I, solanine, solamargine, and tomatidine), galanthamine and others. A plausible structure-function relationship is not apparent, except that all these alkaloids have a quaternary N under physiological conditions, and that an oxygen can be traced 2 to 4 carbons adjacent to the N, similar to the situation in acetylcholine. 

Figure 15 Chemical structure of bisubstrate analog inhibitors of catechol O-methyltransferase.

Fig. 31.30 Reaction mechanism of 0-methylation of catechols catalysed by catechol 0-methyltransferase. The structure of S-adenosylmethionine (SAM) is shown in the insert (from Mannisto and Kaakkola, with permission). ...

Lau, E.Y. and Bruice, T.C. (2000) Comparison of the dynamics for ground-state and transition-state structures of the active site of catechol-O-methyltransferase. J. Am. Chem. Soc. 122 7165-7171. 

The resorcinol residue in (III) has predominantly catered for as a biologically effective replacement of the catechol moiety present in (IV). Importantly, the resorcinol structural analogue (III), in a striking contrast to the catechol (IV), is not a substrate for catechol-O-methyltransferase (COMT)-an extremely important metabolic enzyme and henee, it possesses a marked and pronounced longer duration of action. In fact, terbutaline serves as a useful selective (P2-adrenergic stimulant for the treatment of bronchial asthma and related physiologieal eonditions administered orally). 

Nackley, A.G., et al. Fluman catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 2006, 314, 1930-1933. 

Figure 1, DHS as a chemical building block. Boxed structures are of current industrial value. Catalysts (a) DHS dehydratase (aroZ) (b) reflux (c) catechol-O-methyltransferase (comt) (d) aryl-aldef de dehydrogenase (e) PCA decarboxylase (aroY) (f) catechol 1,2-dioxygenase (catA) (g) Pt/C, H2 (h) p-hydroxybenzoate hydroxylase (pobA ) (i)Cu(OAc) 2, HOAc.

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