Drug Discovery Opinion

Coenzyme A (CoA) is an indispensable cofactor in all living organisms, operating as an acyl carrier and carbonyl-activating group in a variety of biochemical transformations, including fatty acid metabolism. Many bacteria as well as plants and yeast are capable of de novo CoA biosynthesis from aspartate and ketovalerate via pantothenic acid. In contrast, animals and some pathogenic microbes lack a de novo route, and they are totally dependent on scavenging exogenous pantothenic acid (vitamin B5). Biosynthesis of CoA from pantothenic acid is an essential, universal pathway in prokaryotes and eukaryotes, comprising five steps. The third step is the decarboxylation of phosphopantothenoylcysteine to 4′-phosphopantetheine by phosphopantothenoylcysteine decarboxylase (PPCDC).

The gene involved in the formation of PPCDC has previously been identified in plants and humans, where the functional enzyme is a homotrimeric complex. Until now, however, the nature of the enzyme in the yeast Saccharomyces cerevisiae has been unclear. Researchers at Universitat Autònoma de Barcelona (UAB), Spain, in collaboration with the University of Stellenbosch, South Africa, have now unravelled the mystery.

S. cerevisiae appears to contain three genes capable of coding a PPCDC (HAL3, VHS3 and YKL088w), but none of them have been associated with this function. In recent years the UAB group has discovered that the genes HAL3 and VHS3 regulate the activity of a protein phosphatase involved in saline tolerance and in the cell cycle, but the new research has demonstrated that the proteins encoded by these genes have additional functionality. Unlike the plant and human counterparts, the S. cerevisiae PPCDC exists as a heterotrimer. One of these proteins is necessarily coded by the YKL088w gene and the others can be two molecules coded by either HAL3 or VHS3, or one of each. The active site in this case is made up of amino acids from two different proteins: the one coded by YKL088w, which provides a catalytic cysteine, and the one coded by HAL3 or VHS3, which provides a histidine, also essential for the catalysis. So, in S. cerevisiae, HAL3 and VHS3 have apparent multiple functions.

The research, published in Nature Chemical Biology, demonstrates that the heterotrimeric structure of PPCDC can exist in a wide group of yeasts from the Ascomycetes family. This group not only includes yeasts which are used in biotechnology and industry, such as S. cerevisiae and Pichia pastoris, but also potential pathogens such as Candida albicans. The difference between the PPCDC structure in these organisms and that of the human enzyme, together with its essential nature, makes it a potential target for antifungal therapy.

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