Trehalose-6-Phosphate as a Potential Lead Candidate for the Development of Tps1 Inhibitors: Insights from the Trehalose Biosynthesis Pathway in Diverse Yeast Species

• Published in: Applied biochemistry and biotechnology Vol. 181; no. 3; pp. 914 - 924
• Main Authors: Magalhães, Rayne S. S., De Lima, Karina C., de Almeida, Diego S. G., De Mesquita, Joelma F., Eleutherio, Elis C. A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-03-2017; Springer Nature B.V
• Subjects: Antimicrobial agents; Biochemistry; Biodiversity; Biosynthesis; Biotechnology; Candida albicans; Candida albicans - enzymology; Candida albicans - pathogenicity; Candida tropicalis; Candida tropicalis - enzymology; Candida tropicalis - pathogenicity; Candidiasis - drug therapy; Candidiasis - enzymology; Chemistry; Chemistry and Materials Science; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glucosyltransferases - antagonists & inhibitors; Heat tolerance; Infectious diseases; Inhibitor drugs; Lead; Pathogens; Phosphates; Saccharomyces cerevisiae; Saccharomyces cerevisiae - enzymology; Species Specificity; Sugar Phosphates - chemistry; Sugar Phosphates - pharmacology; Trehalose - analogs & derivatives; Trehalose - chemistry; Trehalose - pharmacology; Yeast; Yeasts; Trehalose-6-phosphate; Trehalose-6-phosphate synthase; Inhibition; Candida albicans; Candida tropicalis; Saccharomyces cerevisiae
• ISSN: 0273-2289; 1559-0291
• DOI: 10.1007/s12010-016-2258-6

In some pathogens, trehalose biosynthesis is induced in response to stress as a protection mechanism. This pathway is an attractive target for antimicrobials as neither the enzymes, Tps1, and Tps2, nor is trehalose present in humans. Accumulation of T6P in
Candida albicans
, achieved by deletion of
TPS2
, resulted in strong reduction of fungal virulence. In this work, the effect of T6P on Tps1 activity was evaluated.
Saccharomyces cerevisiae
,
C. albicans
, and
Candida tropicalis
were used as experimental models. As expected, a heat stress induced both trehalose accumulation and increased Tps1 activity. However, the addition of 125 μM T6P to extracts obtained from stressed cells totally abolished or reduced in 50 and 60 % the induction of Tps1 activity in
S. cerevisiae, C. tropicalis
, and
C. albicans
, respectively. According to our results, T6P is an uncompetitive inhibitor of
S. cerevisiae
Tps1. This kind of inhibitor is able to decrease the rate of reaction to zero at increased concentrations. Based on the similarities found in sequence and function between Tps1 of
S. cerevisiae
and some pathogens and on the inhibitory effect of T6P on Tps1 activity observed in vitro, novel drugs can be developed for the treatment of infectious diseases caused by organisms whose infectivity and survival on the host depend on trehalose.