netLibrary - eBook Summary Structure-based Drug Design by ...

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]