Structure, Mechanism, and Substrate Profiles of the Trinuclear Metallophosphatases from the Amidohydrolase Superfamily

Methods in Enzymology
Swapnil V Ghodge, Frank M Raushel

Abstract

The rate of reliable protein function annotation has not kept pace with the rapid advances in genome sequencing technology. This has created a gap between the number of available protein sequences, and an accurate determination of the respective physiological functions. This investigation has attempted to bridge the gap within the confines of members of the polymerase and histidinol phosphatase family of proteins in cog1387 and cog0613, which is related to the amidohydrolase superfamily. The adopted approach relies on using the mechanistic knowledge of a known enzymatic reaction, and discovering functions of closely related homologs using various tools including bioinformatics and rational library screening. The initial enzymatic reaction was that of L-histidinol phosphate phosphatase. Extensive structural, biochemical, and bioinformatic analysis of enzymes capable of hydrolyzing L-histidinol phosphate provided useful insights in predicting substrates and mechanistic studies of related enzymes. This led to the discovery of unprecedented catalytic functions such as a cyclic phosphate dihydrolase that specifically hydrolyzed a cyclic phosphodiester to inorganic phosphate and a vicinal diol; a phosphoesterase that hydrolyzes the 3...Continue Reading

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