Crystal structure of Leishmania donovani glucose 6-phosphate dehydrogenase reveals a unique N-terminal domain

Abstract

Since unicellular parasites highly depend on NADPH as a source for reducing equivalents, the pentose phosphate pathway, especially the first and rate-limiting NADPH-producing enzyme glucose 6-phosphate dehydrogenase (G6PD), is considered an excellent antitrypanosomatid drug target. Here we present the crystal structure of Leishmania donovani G6PD (LdG6PD) elucidating the unique N-terminal domain of Kinetoplastida G6PDs. Our investigations on the function of the N-domain suggest its involvement in the formation of a tetramer that is completely different from related Trypanosoma G6PDs. Structural and functional investigations further provide interesting insights into the binding mode of LdG6PD, following an ordered mechanism, which is confirmed by a G6P-induced domain shift and rotation of the helical N-domain. Taken together, these insights into LdG6PD contribute to the understanding of G6PDs’ molecular mechanisms and provide an excellent basis for further drug discovery approaches.

Structural basis of the allosteric regulation of cyanobacterial glucose-6-phosphate dehydrogenase by the redox sensor OpcA

“…Additionally, we detected minor amounts of other oligomeric states of G6PDH, including trimers and larger complexes of interacting tetra-and trimers. However, we did not observe monomers or dimers, as previously reported for homologous enzymes (11)(12)(13)(14).…”

Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation

“…Among the key mechanisms to counter oxidative stress is the diversion of the intermediate products of glycolysis to the oxidative PPP [ 38 ]. G6PD, the first NADPH-producing enzyme in the PPP, is considered the predominant contributor to the NADPH pool [ 39 ]. G6PD overexpression in multiple cancers is associated with a poor disease prognosis [ 7 ].…”

Challenges in drug discovery and description targeting Leishmania spp.: enzymes, structural proteins, and transporters

“…Although the enzyme Tb6PGDH has been characterized and its crystal structure has been reported (31,32), the enzymes Lm6PGDH and Tc6PGDH seem to be unstable, and the conditions to obtain their crystal structure have not been possible to define; however, such structure, in complex with NADP(H), has recently been obtained for L. donovani (Ld6PGD) enzyme (33).…”

“…The C-terminal tail comprised the Cterminal residues of a subunit; it penetrated domain II of the adjacent subunit, thus joining the two monomers (Figure 1). The three-dimensional crystal structure of the L. donovani (Ld6PGD) in complex with NADP(H) has been recently solved, revealing a previously unknown conformation of NADPH (33).…”