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Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Toward the Development of Inhibitors Directed against Mammalian DDAH Proteins: Considerations from Homology Modeling of DDAH-2 and DDAH Activity Tracing in Tissue Homogenate

Author(s): Markus Knipp

Volume 4 , Issue 8 , 2007

Page: [570 - 579] Pages: 10

DOI: 10.2174/157018007782794572

Price: $65

Abstract

The cysteine hydrolase N ω,N ω-dimethyl-L-arginine dimethylaminohydrolase-1 (DDAH-1) is an important regulator of NO production through the degradation of endogenous Nω-methylated arginines, that are competitive inhibitors for nitric oxide synthase (NOS). Consequently, DDAH-1 is a target for pharmacological drug design to regulate NO production. The appearance of a second isoform DDAH-2, which was assigned through sequence comparison, requires detailed knowledge about the properties of both proteins. This study represents the first attempt for a structural and functional characterization of DDAH-2. However, lack in enzymatic activity together with structural consideration based on a homology model places the designation as a DDAH enzyme into question. On the other hand, it is shown that DDAH-2 is a substrate for two protein-arginine methyltransferases, CARM-1 and PRMT-6, which supports the participation of DDAH-2 in the metabolism of side-chain methylated arginines.

Keywords: Arginine methylation, CARM-1, DDAH, Dimethylarginine dimethylaminohydrolase, g6a, PRMT-6


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