Targeting UDP-Galactopyranose Mutases from Eukaryotic Human Pathogens

Abstract

UDP-Galactopyranose mutase (UGM) is a unique flavin-dependent enzyme that catalyzes the conversion of UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). The product of this reaction is the precursor to Galf, a major component of the cell wall and of cell surface glycoproteins and glycolipids in many eukaryotic and prokaryotic human pathogens. The function of UGM is important in the virulence of fungi, parasites, and bacteria. Its role in virulence and its absence in humans suggest that UGM is an ideal drug target. Significant structural and mechanistic information has been accumulated on the prokaryotic UGMs; however, in the past few years the research interest has shifted to UGMs from eukaryotic human pathogens such as fungi and protozoan parasites. It has become clear that UGMs from prokaryotic and eukaryotic organisms have different structural and mechanistic features. The amino acid sequence identity between these two classes of enzymes is low, resulting in differences in oligomeric states, substrate binding, active site flexibility, and interaction with redox partners. However, the unique role of the flavin cofactor in catalysis is conserved among this enzyme family. In this review, recent findings on eukaryotic UGMs are discussed and presented in comparison with prokaryotic UGMs.

UDP-galactopyranose mutases from Leishmania species that cause visceral and cutaneous leishmaniasis

“…Clearly, substrate affinity is enhanced in the reduced forms of the enzymes. The results are consistent with the previously reported values for other UGMs [10, 16, 37]. In Tc UGM and Af UGM, we have shown that reduction of the enzymes is coupled to conformational changes, mainly in a region known as the histidine loop [18, 22, 38].…”

“…Therefore, enzymes in the Gal f biosynthetic pathway are potential targets for the development of novel anti-parasitic drugs. One important target is the enzyme UDP-galactopyranose mutase (UGM), which catalyzes the conversion of UDP-galactopyranose to form UDP-Gal f (Scheme 1) [9,10]. The importance of this enzyme in kinetoplastids has been validated by demonstration that deletion of the UGM gene leads to greatly reduced virulence in L. major [11].…”

Identification of the NAD(P)H Binding Site of Eukaryotic UDP-Galactopyranose Mutase

“…In particular, eukaryotic UGMs have emerged recently as targets for the design of antifungal, antitrypanosomal, and antileishmanial agents. 2–4 For example, gene deletion studies have shown that UGM is essential for the virulence of the pathogenic fungus Aspergillus fumigatus and the protozoan parasite Leishmania major . 5,6 Thus, there is interest in characterizing the ligand binding sites of UGMs to facilitate drug discovery.…”

Deciphering the sugar biosynthetic pathway and tailoring steps of nucleoside antibiotic A201A unveils a GDP- l -galactose mutase

“…These findings have highlighted the critical role of UGMs in Galf biosynthesis, especially as relates to virulence, cellular adhesion, parasite viability, and proper developmental processes (8)(9)(10)(11). It has been proposed that during the formation of UDP-Galf, a flavin adenine dinucleotide (FAD)-iminium ion intermediate is formed through nucleophilic addition that facilitates galactose ring opening and contraction (5,(12)(13)(14)(15)(16). Three dimensional structures for members of the UGM family have been determined by X-ray crystallography in free form and in complex with various substrates, as well as in association with both oxidized and reduced forms of FAD (12,13,(17)(18)(19).…”

“…Notably, a covalent FAD-Galp intermediate involved in the UGM reaction has recently yielded to elucidation by X-ray crystallography shedding significant insight into UGM catalysis (20). Consequently, UGM is a potential antimicrobial drug target (3,16).…”