6-Phosphogluconate dehydrogenase and its crystal structures

Abstract

6-Phosphogluconate dehydrogenase (6PGDH; EC 1.1.1.44) catalyses the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate in the context of the oxidative part of the pentose phosphate pathway. Depending on the species, it can be a homodimer or a homotetramer. Oligomerization plays a functional role not only because the active site is at the interface between subunits but also due to the interlocking tail-modulating activity, similar to that of isocitrate dehydrogenase and malic enzyme, which catalyse a similar type of reaction. Since the pioneering crystal structure of sheep liver 6PGDH, which allowed motifs common to the β-hydroxyacid dehydrogenase superfamily to be recognized, several other 6PGDH crystal structures have been solved, including those of ternary complexes. These showed that more than one conformation exists, as had been suggested for many years from enzyme studies in solution. It is inferred that an asymmetrical conformation with a rearrangement of one of the two subunits underlies the homotropic cooperativity. There has been particular interest in the presence or absence of sulfate during crystallization. This might be related to the fact that this ion, which is a competitive inhibitor that binds in the active site, can induce the same 6PGDH configuration as in the complexes with physiological ligands. Mutagenesis, inhibitors, kinetic and binding studies, post-translational modifications and research on the enzyme in cancer cells have been complementary to the crystallographic studies. Computational modelling and new structural studies will probably help to refine the understanding of the functioning of this enzyme, which represents a promising therapeutic target in immunity, cancer and infective diseases. 6PGDH also has applied-science potential as a biosensor or a biobattery. To this end, the enzyme has been efficiently immobilized on specific polymers and nanoparticles. This review spans the 6PGDH literature and all of the 6PGDH crystal structure data files held by the Protein Data Bank.

An imine reductase that captures reactive intermediates in the biosynthesis of the indolocarbazole reductasporine

“…Despite this large deviation, the backbone traces of the overall quaternary structure of the dimer is maintained between IREDs and β HADs. The related 6-phosphogluconate dehydrogenases shares a similar fold to β HADs, where the helical bundle of a 6-phosphogluconate dehydrogenases protomer has a circa 130 amino acid C-terminal extension which replicates the fold of an interacting β HAD dimer ( 39 ).…”

New Insights into the Cooperativity and Dynamics of Dimeric Enzymes

“…451 Similarly, 6-phosphogluconate dehydrogenase (6PGDH; EC 1.1.1.44) catalyzes the oxidative decarboxylation of 6-phosphogluconate (6PG) to ribulose 5-phosphate (Ru5P) with NADPH in the oxidative pathway of the pentose phosphate pathway (PPP). 93 In Trypanosoma brucei, 6PGDH has a dimer−tetramer equilibrium with a tetramer's specific activity more than three times higher than that of the dimer. Tetramerization is promoted by NADPH, while 6PG is able to antagonize the NADPH effect.…”

“…Certain enzymes are only biologically active when in homodimeric form, ,− as in the case of the psychrophilic acyl aminoacyl peptidase from Sporosarcina psychrophila (spAAP). The enzyme’s monomer form is unstable and inactive .…”

“…The enzyme’s monomer form is unstable and inactive . This phenomenon is more common when the catalytic pocket is situated at the dimerization interface, ,, such as 3-hydroxyisobutyrate dehydrogenase from Bacillus cereus (bcHIBADH), where an intersubunit cleft forms a putative active site accommodating cofactors (NAD + ) and substrate mimetics . Similarly, outer membrane phospholipase A (OMPLA) also dimerizes to form two substrate-binding pockets at the dimer interface, in addition to functional oxyanion holes that are absent in monomeric OMPLA …”

“…Pyruvate carboxylase catalyzes the carboxylation of pyruvate to produce oxaloacetate, Acetyl-CoA stabilizes the biotin carboxylase domain of pyruvate carboxylase in a catalytic conformation . Similarly, 6-phosphogluconate dehydrogenase (6PGDH; EC 1.1.1.44) catalyzes the oxidative decarboxylation of 6-phosphogluconate (6PG) to ribulose 5-phosphate (Ru5P) with NADPH in the oxidative pathway of the pentose phosphate pathway (PPP) . In Trypanosoma brucei , 6PGDH has a dimer–tetramer equilibrium with a tetramer’s specific activity more than three times higher than that of the dimer.…”