Multisite Promiscuity in the Processing of Endogenous Substrates By Human Carboxylesterase 1

Journal Article · Tue Jan 16 04:00:00 EST 2007 · J.Mol.Biol.363:201, 2006

OSTI ID:897737

Bencharit, S; Edwards, C C; Morton, C L; Howard-Williams, E L; Kuhn, P; Potter, P M; Redinbo, M R

Human carboxylesterase 1 (hCE1) is a drug and endobiotic-processing serine hydrolase that exhibits relatively broad substrate specificity. It has been implicated in a variety of endogenous cholesterol metabolism pathways including the following apparently disparate reactions: cholesterol ester hydrolysis (CEH), fatty acyl Coenzyme A hydrolysis (FACoAH), acyl-Coenzyme A:cholesterol acyltransfer (ACAT), and fatty acyl ethyl ester synthesis (FAEES). The structural basis for the ability of hCE1 to perform these catalytic actions involving large substrates and products has remained unclear. Here we present four crystal structures of the hCE1 glycoprotein in complexes with the following endogenous substrates or substrate analogues: Coenzyme A, the fatty acid palmitate, and the bile acids cholate and taurocholate. While the active site of hCE1 was known to be promiscuous and capable of interacting with a variety of chemically distinct ligands, these structures reveal that the enzyme contains two additional ligand-binding sites and that each site also exhibits relatively non-specific ligand-binding properties. Using this multisite promiscuity, hCE1 appears structurally capable of assembling several catalytic events depending, apparently, on the physiological state of the cellular environment. These results expand our understanding of enzyme promiscuity and indicate that, in the case of hCE1, multiple non-specific sites are employed to perform distinct catalytic actions.

• Research Organization: Stanford Linear Accelerator Center (SLAC)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC02-76SF00515
• OSTI ID: 897737
• Report Number(s): SLAC-REPRINT-2006-180
• Journal Information: J.Mol.Biol.363:201, 2006, Journal Name: J.Mol.Biol.363:201, 2006
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
BILE ACIDS
CARBOXYLESTERASES
CARBOXYLIC ACIDS
CHOLESTEROL
COENZYMES
CRYSTAL STRUCTURE
ENZYMES
ESTERS
GLYCOPROTEINS
HYDROLASES
HYDROLYSIS
METABOLISM
Other
OTHER
SERINE
SPECIFICITY
SUBSTRATES
SYNTHESIS