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This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada.

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Introduction

Mevalonate diphosphate decarboxylase (MDD) is an important enzyme required for the biosynthesis of cholesterol and other isoprenoids in mammals, bacteria, yeast and fungi ^[1]. MDD is a member of the GHMP (Galactokinase, Homoserine kinase, mevalonate kinase and phosphomevalonate kinase) enzyme family, and is responsible for the conversion of mevalonate diphosphate to isopentenyl pyrophosphate with the help of 1 ATP molecule^{[1] [2]}. Even though the kinases in the GHMP family differ in quaternary structure and ability to bind a wide variety of substrates, they share a characteristic alpha/beta fold and similar sequences ^{[1] [3]}. Some GHMP kinases exist as dimers, some as tetramers and some as monomers ^[1]. The amino acid residues in MDD are highly conserved across all species, indicating the specific important activity of the enzyme ^[1].

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Structure

Mevalonate diphosphate decarboxylase exists as a symmetrical dimer^{[1] [2] [3]} . The C-terminal domains of each monomer are symmetrically oriented towards one another around a solvent-filled channel ^[1]. The dimer is stabilized between alpha helices 6 and 10 on the monomers, and also through salt bridge interactions, tyrosine and proline stacking, and hydrophobic interactions ^[1]. The interface between the monomers is very small, with only 7% of the total surface area of the monomer engaged in the interface interaction ^[2]. This small interface between monomers is a characteristic of GHMP kinases ^[2]. Each monomer consists of a single polypeptide chain with 331 amino acid residues. Each polypeptide chain has 13 alpha helices and 15 beta chains. The active site on each monomer is a deep, highly charged cleft made up seven segments of polypeptide chain, which is located away from the other monomer, and is unaffected by dimerization ^[1]. An ATP binding polypeptide segment called the P loop is also located near the active site ^[1]. A total of 19 amino acid residue side chains are involved with substrate binding in the active site ^[1].

Reaction

The mevalonate pathway encompasses 3 different enzymes that convert mevalonate to isopentenyl pyrophosphate, which is an important building block for all isoprenoids ^[4]