Structure of Enzyme for Trehalose Synthesis May Promote Drug Development

Trehalose acts to protect the fungi from the high temperatures they experience while trying to colonize the human organism. The enzymes that synthesize trehalose are not found in humans, and thus serve as potential targets for novel antifungal drugs.

Investigators at Duke University (Durham, NC, USA) used x-ray crystallography to establish multiple structures for one of the trehalose biosynthetic enzymes, trehalose-6-phosphate phosphatase (Tps2), from Candida albicans.

In a paper published in the June 15, 2016, online edition of the journal Proceedings of the [U.S.] National Academy of Sciences the investigators said that these structures and germane in vivo and biochemical studies revealed the significance of the Tps2 N-terminal domain in fungal cellular stress responses and the conformational flexibility of the Tps2 C-terminal domain that imposed exquisite substrate specificity and permitted efficient catalysis.

"We found that the active site of this enzyme is identical in each of these pathogenic fungi, so they all use the same mechanism and have the same residues that are necessary for the production of trehalose," said senior author Dr. Richard G. Brennan, professor of biochemistry at Duke University. "By targeting those active sites, we hope to create a drug with broad-spectrum effect. If you could kill one fungus, you are going to kill them all; at least if you can get the drug inside."

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