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Document Figure 1 The rationale of COMT inhibition as adjunct in the L-dopa therapy of Parkinson's disease (reproduced by permission from COMT News, Issue 1, Orion Corporation, Orion Pharma, 1994). Page 344 research in pharmaceutical companies has been carried out to develop new potent, selective, and orally active COMT inhibitors. Some of them (e.g., entacapone), are now in final clinical trials and the results have been promising. The rationale of COMT inhibition can be seen in Figure 1. It can be concluded that COMT inhibition in peripheral tissues improves the brain entry of L-dopa and decreases the formation of 3-OMD. The dose of L-dopa can be lowered and the dose interval prolonged. Also a decrease of the fluctuations of dopamine formation has been observed. The inhibition of COMT seems to be the next step in improving the L-dopa therapy of Parkinson's disease. This paper discusses the structure-based approach for the understanding of the enzyme function and inhibitor design. II. The Enzyme A. Physiological Role of COMT Catechol O-methyltransferase (COMT, EC 2.1.1.6) was originally detected in rat liver extracts [1]. Since then, COMT has been found in many species: http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_344.html (1 of 2) [4/5/2004 5:27:34 PM]
Document Figure 2 The reaction catalyzed by catechol O-methyltransferase. Dopamine: R=CH 2-CH 2-NH 2; L-dopa: R=CH 2-CH(NH 2)-COOH. animals, plants, and procaryotes [2]. In mammals the highest COMT activities have been found in the liver and kidney, but COMT is common in almost all mammalian tissues [2–4]. Page 345 The COMT enzyme catalyzes the transfer of the methyl group from the coenzyme S-adenosyl-Lmethionine (AdoMet) to one of the phenolic hydroxyl groups of a catechol or substituted catechol [1] (Figure 2). The presence of magnesium ions is required for the catalysis. The reaction products are Omethylated catechol and S-adenosyl-L-homocysteine (AdoHcy). Physiological substrates of COMT are catecholamine neurotransmitters, dopamine, noradrenaline, and adrenaline, and some of their metabolites. The COMT enzyme inactivates catecholic steroids such as 2-hydroxyestradiol, drugs with a catechol structure such as L-dopa, and a large number of other catechol compounds [1,2,5–7]. The general physiological function of COMT is the inactivation of biologically active or toxic catechols. A schematic view of the major catecholamine pathways in the brain is shown in Figure 3. L-Dopa is the dopamine precursor used in the treatment of Parkinson's disease [8]. B. Primary Structures There are no isoenzymes of COMT known in different mammalian tissues. Two distinct forms of COMT have been found: one is soluble (S-COMT) and the other membrane bound (MB-COMT) [9,10]. Both soluble and membrane-bound COMT have been cloned and characterized [11–16]. The soluble and membrane-bound COMT are coded by one gene using two separate promoters [17]. The soluble COMT contains 221 amino acids, whereas the membrane-bound form has a 50-(human) or 43-(rat) residueslong amino-terminal extension containing the hydrophobic membrane anchor region. The sequences of COMT enzymes from different species are highly similar (see Figure 4). The soluble human protein is 81% identical with the rat enzyme. The 165-amino-acids-long fragment of porcine COMT has 82% homology with the human http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_345.html [4/5/2004 5:27:37 PM]
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Structure-based Drug Design 14 Stru
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