Division of labor in transhydrogenase by alternating proton translocation and hydride transfer

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Science  09 Jan 2015:
Vol. 347, Issue 6218, pp. 178-181
DOI: 10.1126/science.1260451

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Dueling dimers serve dual purposes

Both bacteria and mitochrondria produce NADPH for amino acid biosynthesis and to remove reactive oxygen species. The enzyme that makes NADPH must translocate a proton across the membrane and transfer a hydride from NADH to NADP+—processes that happen some 40 Å apart. To understand this complex geometry, Leung et al. solved the structures of the entire transhydrogenase enzyme and the membrane domain from the bacterium Thermus thermophilus (see the Perspective by Krengel and Törnroth-Horsefield). The entire enzyme exists as a dimer, with the two membrane domains in alternate orientations. One of the membrane domains interacts with the membrane component for proton translocation, whereas the other domain exchanges hydride with NAD(H) in another large soluble domain.

Science, this issue p. 178; see also p. 125


NADPH/NADP+ (the reduced form of NADP+/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 Å crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 Å crystal structure of the entire enzyme (holo-TH). The membrane domain crystallized as a symmetric dimer, with each protomer containing a putative proton channel. The holo-TH is a highly asymmetric dimer with the NADP(H)–binding domain (dIII) in two different orientations. This unusual arrangement suggests a catalytic mechanism in which the two copies of dIII alternatively function in proton translocation and hydride transfer.

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