This page is for Alex Waters' fumarase page.
Fumarase is a tetrameric enzyme which is responsible for catalyzing the hydration and dehydration of L-malate and fumarate. As an enzyme that has been well characterized in the lab, many crystallographic studies have been done to describe the active site of this enzyme. Several of these studies have been done using inhibitors like pyromellitic acid and beta-trimethylsilyl maleate. These studies produced different results. An area called the "tungsten site", which formed between atoms of three of the four subunits was determined to be the binding site of some of these inhibitors and was called the "A-site". This site exists deep in the enzyme. However, other studies provided data indicating another site, called the "B-site" which also bound the inhibitors and was composed of atoms from one subunit only and is closer to the surface of the enzyme. Both the A-site and the B-Site make use of a Histidine residue to catalyze the reaction. In order to determine the correct active site of fumarase, two mutants were created which altered the histidines responsible for catalyzing the reaction at each site. H188 was expected to change catalytic activity if the A-site was the active site and H129 would change catalytic activity if the B-site was the active site. By measuring the activity of each mutant and comparing it to the wild-type enzyme, is was determined that the A-site of fumarase is the active site, as the activity of this mutant was nearly 200 times less than the wild type, while the B-site's activity remained roughly equal to the wild-type. Crystal structures of these two mutants further confirmed that the A-site is the active site.
Function
Disease
Relevance
Structural highlights
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