4uup

Reconstructed ancestral trichomonad malate dehydrogenase in complex with NADH, SO4, and PO4

spinqualitylabelsall models 4uup, resolution 1.54Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4uup is a 2 chain structure with sequence from Synthetic construct sequences. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NAI, PO4, SO4 NonStd Res: OCS Related: 4uul, 4uum, 4uun, 4uuo Activity: Malate dehydrogenase, with EC number 1.1.1.37 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Lactate and malate dehydrogenases (LDH and MDH) are homologous, core metabolic enzymes common to nearly all living organisms. LDHs have evolved convergently from MDHs at least four times, achieving altered substrate specificity by a different mechanism each time. For instance, the LDH of anaerobic trichomonad parasites recently evolved independently from an ancestral trichomonad MDH by gene duplication. LDH plays a central role in trichomonad metabolism by catalyzing the reduction of pyruvate to lactate, thereby regenerating the NAD+ required for glycolysis. Using ancestral reconstruction methods, we identified the biochemical and evolutionary mechanisms responsible for this convergent event. The last common ancestor of these enzymes was a highly specific MDH, similar to modern trichomonad MDHs. In contrast, the LDH lineage evolved promiscuous activity by relaxing specificity in a gradual process of neofunctionalization involving one highly detrimental substitution at the "specificity residue" (R91L) and many additional mutations of small effect. L91 has different functional consequences in LDHs and in MDHs, indicating a prominent role for epistasis. Crystal structures of modern-day and ancestral enzymes show that the evolution of substrate specificity paralleled structural changes in dimerization and alpha-helix orientation. The relatively small "specificity residue" of the trichomonad LDHs can accommodate a range of substrate sizes and may permit solvent to access the active site, both of which promote substrate promiscuity. The trichomonad LDHs present a multi-faceted counterpoint to the independent evolution of LDHs in other organisms and illustrate the diverse mechanisms by which protein function, structure, and stability coevolve. This article is protected by copyright. All rights reserved. Gradual neofunctionalization in the convergent evolution of trichomonad lactate and malate dehydrogenases.,Steindel PA, Chen EH, Wirth JD, Theobald DL Protein Sci. 2016 Feb 17. doi: 10.1002/pro.2904. PMID:26889885 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Malate dehydrogenase

Proteopedia Page Contributors and Editors (what is this?)

OCA