Homework 5 Chem 157

Topics: Enzyme, Adenosine triphosphate, Signal transduction Pages: 2 (379 words) Published: June 6, 2013
Rafa Mwais
Professor Hermann
Chem 157
Paper #5
May 28,2013

Crystal Structure of the Catalytic Portion of Human HMG-CoA Reductase

3-hydroxy-3methylglutaryl-CoA reductase (HMGR) catalyzes the formation of mevalonate in the biosynthesis of sterols and isoprenoids. The activity of this enzyme is regulated physiologically through synthesis, degradation and phosphorylation to maintain to maintain the concentration of the mevalonate-derived products. Transcription and translation of HMGR increase when the concentrations of products of mevalonate pathway are low while on the other hand when the concentrations are high, the intracellular HMGR concentration decreases rapidly. The third level of regulation is achieved by phosphorylation of S872 by AMP-activated protein Kinase, which decreases the enzyme’s activity.

Three crystal structures of the catalytic portion of human HMGR in complexes with HMG-CoA, with HMG and CoA, and with HMG, CoA and NADP+, provide the detailed view of the enzyme active site. Catalytic portions of human HMGR form tetramers. The individual monomers wind around each other in an intricate fashion. In the tetramer, the monomers are arranged in two dimers; each of which contains two active sites, which are formed by residues from both monomers (alpha and beta). The tetramer has a total of four active sites where two of them are formed by the first dimer (1), and the second dimer (2) forms the other two.

HMGR activity is regulated by phosphorylation that a pair of enzymes controls its levels: AMP-activated protein Kinase and HMG-CoA phosphorylase. Phosphorylation at S872 reduces the activity of the protein. A similar effect can be observed when S872 is mutated to an aspartate. Because S872 is located close to the catalytic residue H866 in the primary structure, it was proposed that the phosphoserine interacts directly with H866 and abstracts its imidazolium proton. S872 is not close to H866, but in the vicinity of the...
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