The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria

White, Scott A.; Peake, Sarah J.; McSweeney, Seán; Leonard, Gordon A.; Cotton, Nick P.J.; Jackson, John L.

doi:10.1016/s0969-2126(00)00075-7

Cited by 65 publications

(102 citation statements)

References 60 publications

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“…The complex can catalyze a very fast redox reaction between NAD(H) on dI and NADP(H) on dIII (34), but evidently at just one of the two interfaces that can form in the complete, "hexameric" enzyme (dI 2 dII 2 dIII 2 ). It was proposed that, in the complete enzyme, there are conformational changes that alternately bring together the two dI/dIII interfaces to permit the redox reaction (23). These conformational changes are coupled to proton translocation across the membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Note also that the side-chain amide of Gln 132 , from the RQD loop of dI, makes an H-bond across the interface with the 2Ј-OH of the nicotinamide ribose of NADP(H). Loop E (the "lid") appears to be particularly important in maintaining the high affinity of isolated dIII for NADP(H) (23); its location over the nucleotide, with which it makes numerous H-bonds, appears to be an essential feature of the occluded state, and it is presumably retracted in the formation of the open state of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…Those from R. rubrum have been studied in the most detail (11)(12)(13)(14), but the equivalent components from E. coli (12,15), bovine (16,17), human (18), and Entamoeba histolytica (19) transhydrogenases have similar properties. High resolution structures of both dI (20) and dIII (21)(22)(23)(24) have now been published. Remarkably, a simple mixture of dI and dIII proteins, even from different species, forms a complex that catalyzes transhydrogenation.…”

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confidence: 99%

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The Heterotrimer of the Membrane-peripheral Components of Transhydrogenase and the Alternating-site Mechanism of Proton Translocation

Venning¹,

Rodrigues²,

Weston³

et al. 2001

Journal of Biological Chemistry

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Transhydrogenase undergoes conformational changes to couple the redox reaction between NAD(H) and NADP(H) to proton translocation across a membrane. The protein comprises three components: dI, which binds NAD(H); dIII, which binds NADP(H); and dII, which spans the membrane. Experiments using isothermal titration calorimetry, analytical ultracentrifugation, and small angle x-ray scattering show that, as in the crystalline state, a mixture of recombinant dI and dIII from Rhodospirillum rubrum transhydrogenase readily forms a dI 2 dIII 1 heterotrimer in solution, but we could find no evidence for the formation of a dI 2 dIII 2 tetramer using these techniques. The asymmetry of the complex suggests that there is an alternation of conformations at the nucleotidebinding sites during proton translocation by the complete enzyme. The characteristics of nucleotide interaction with the isolated dI and dIII components and with the dI 2 dIII 1 heterotrimer were investigated. (a) The rate of release of NADP ؉ from dIII was decreased 5-fold when the component was incorporated into the heterotrimer. (b) The binding affinity of one of the two nucleotide-binding sites for NADH on the dI dimer was decreased about 17-fold in the dI 2 dIII 1 complex; the other binding site was unaffected. These observations lend strong support to the alternating-site mechanism.Transhydrogenase, found in the cytoplasmic membranes of bacteria, and in the inner membranes of animal mitochondria, couples the redox reaction between NAD(H) and NADP(H) to the translocation of protons.Its function in energy metabolism, biosynthesis, and detoxification has been discussed at length (1, 2). In different organisms (and possibly in different tissues of the same organism) transhydrogenase can either utilize the proton electrochemical gradient (⌬p) to drive reduction of NADP ϩ by NADH, or it can use NADPH oxidation by NAD ϩ to augment ⌬p formation. Energy coupling in transhydrogenase is indirect. In the forward direction (Reaction 1), protein conformational changes accompanying proton translocation bring together the nicotinamide rings of the bound nucleotides to allow the redox reaction (3). This "binding-change mechanism" may share common features with energy coupling in some ion-translocating ATPases. More generally, transhydrogenase has a number of properties that make it an excellent model for understanding the principles of operation of conformationally linked pumps in biology.The polypeptide organization of transhydrogenases varies between species, but the arrangement of the three components, dI, dII, and dIII, is essentially the same in all (Fig. 1). NAD(H) binds to dI, and NADP(H) binds to dIII; these two components protrude from the membrane (into the bacterial cytoplasm or mitochondrial matrix). The dII component spans the membrane, probably in 13 or 14 transmembrane helices (reviewed in Ref. 4). There is cross-linking and hydrodynamic evidence that both the bovine (5, 6) and Escherichia coli (7) transhydrogenases have two copies each of dI, dII, and dIII...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Heterotrimer of the Membrane-peripheral Components of Transhydrogenase and the Alternating-site Mechanism of Proton Translocation

Venning¹,

Rodrigues²,

Weston³

et al. 2001

Journal of Biological Chemistry

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“…High-resolution structures of isolated dI [13][14][15] and dIII [16][17][18], and that of a dI-dIII complex [19][20][21], have been published during the last decade, and have afforded insights particularly into nucleotide binding and the hydride transfer step. The recent structure of the membrane-spanning dII at 2.8 Å A 0 resolution, and of the holo-enzyme at 6.9 Å A 0 from Thermus thermophilus [22], provide clues as to how hydride transfer from NADH to NADP + at the interface of dI and dIII is coupled to proton translocation through dII.…”

Section: The DI Dii and Diii Components Of Transhydrogenasementioning

confidence: 99%

“…Studies on these and other mutants in loop E and helix D/loop D of isolated E. coli dIII reveal further consequences of interactions of the protein with NADP + and NADPH [33,34]. In crystal structures the equivalent residues to EcbD392 form hydrogen bonds with the pyrophosphate and a ribose hydroxyl group of bound NADP + /NADPH [16,17]. Its unusually high pK a , sensitive to the redox state of the bound nucleotide [35][36][37], and the fact that its substitution results in a failure in NADP + /NADPH binding [33] to isolated dIII, indicate an important catalytic role for this residue.…”

Section: The DI Dii and Diii Components Of Transhydrogenasementioning

confidence: 99%

Review and Hypothesis. New insights into the reaction mechanism of transhydrogenase: Swivelling the dIII component may gate the proton channel

et al. 2015

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Edited by Peter BrzezinskiKeywords: Transhydrogenase Membrane-protein structure Nicotinamide nucleotide Proton-pump Proton-gating a b s t r a c tThe membrane protein transhydrogenase in animal mitochondria and bacteria couples reduction of NADP + by NADH to proton translocation. Recent X-ray data on Thermus thermophilus transhydrogenase indicate a significant difference in the orientations of the two dIII components of the enzyme dimer (Leung et al., 2015). The character of the orientation change, and a review of information on the kinetics and thermodynamics of transhydrogenase, indicate that dIII swivelling might assist in the control of proton gating by the redox state of bound NADP + /NADPH during enzyme turnover.

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The transferred translocases: An old wine in a new bottle

Balaji

2021

Biotech and App Biochem

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The role of translocases was underappreciated and was not included as a separate class in the enzyme commission until August 2018. The recent research interests in proteomics of orphan enzymes, ionomics, and metallomics along with high‐throughput sequencing technologies generated overwhelming data and revamped this enzyme into a separate class. This offers a great opportunity to understand the role of new or orphan enzymes in general and specifically translocases. The enzymes belonging to translocases regulate/permeate the transfer of ions or molecules across the membranes. These enzyme entries were previously associated with other enzyme classes, which are now transferred to a new enzyme class 7 (EC 7). The entries that are reclassified are important to extend the enzyme list, and it is the need of the hour. Accordingly, there is an upgradation of entries of this class of enzymes in several databases. This review is a concise compilation of translocases with reference to the number of entries currently available in the databases. This review also focuses on function as well as dysfunction of translocases during normal and disordered states, respectively.

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The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria

Cited by 65 publications

References 60 publications

The Heterotrimer of the Membrane-peripheral Components of Transhydrogenase and the Alternating-site Mechanism of Proton Translocation

The Heterotrimer of the Membrane-peripheral Components of Transhydrogenase and the Alternating-site Mechanism of Proton Translocation

Review and Hypothesis. New insights into the reaction mechanism of transhydrogenase: Swivelling the dIII component may gate the proton channel

The transferred translocases: An old wine in a new bottle

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