Substrate Binding Site and the Role of the FLAP Loop in Candida rugosa Lipase, A Close Relative of Acetylcholinesterase
Candida rugosa lipase belongs to a large lipase/esterase family of evolutionarily related hydrolytic enzymes identified on the basis of their amino acid homology (Krejci et al., 1991; Gentry et al., 1991; Cygler et al., 1993). Other members of this family include acetyl- and butyrylcholinesterases, carboxylesterases, cholesterol esterases, etc. The catalytic apparatus of these enzymes is composed of a Ser-His-Glu/Asp triad. Apart from the hydrolytic enzymes there are also other proteins with domains that clearly belong to this family but are devoid of the hydrolytic activity, eg. neurotactin, thyroglobulin, etc. The amino acid identity within this family varies from ∼16%, for distantly related proteins, to 97% and a number of subfamilies are clearly distinguishable (Cygler et al., 1993). To date, the crystal structures of three of these proteins have been determined: Torpedo californica acetylcholinesterase (AChE, Sussman et al., 1991), Geotrichum candidum lipase (GCL, Schrag et al., 1991) and Candida rugosa lipase (CRL, Grochulski et al., 1993). These three enzymes display great similarities in their three-dimensional structures and provide prototypic models for other members of this large family. They belong to the α/β hydrolase fold superfamily (Ollis et al., 1992). The two lipases, which share ∼40% sequence identity, have also more similar structures. Approximately 90% of their Ca atoms superimpose with a root-mean-square (rms) deviation of 1.4Å. Comparison of GCL and TcAChE (∼25% identity) shows that ∼75% of their Ca atoms can be superimposed with a 1.9Å rms, including the catalytic apparatus composed of a Ser-His-Glu triad. Yet despite their significant structural similarity TcAChE and GCL/CRL hydrolyze very different substrates. While the lipases break down water insoluble triglycerides, the acetylcholinesterase hydrolyzes the water soluble neurotransmitter, acetylcholine.
KeywordsDepression Catalysis Lipase Cysteine Serine
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