The NNT gene contains 26 exons and encodes a transhydrogenase protein that is ~109 kDa in molecular weight and is involved in antioxidant defense in the mitochondria. Two alternatively spliced variants, encoding the same protein, have been found for this gene.[7]
Structure
Transhydrogenases including NNT can exist in an ‘open’ conformation,[8] where substrates can bind and products can dissociate, in which the dihydronicotinamide and nicotinamide rings are held apart to block hydride transfer. It can exist in an ‘occluded’ conformation, where the substrates are moved into apposition to permit redox chemistry.[8] The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane.[9] X-ray crystallography structure of the protein shows that proton pumping is probably coupled to changes in the binding affinities of dIII for NADP(+) and NADPH. The first betaalphabetaalphabeta motif of dIII contains a Gly-X-Gly-X-X-Ala/Val fingerprint, whereas the nicotinamide ring of NADP(+) is located on a ridge where it can interact with NADH on the dI subunit.[9]
Function
NAD(P) transhydrogenase, mitochondrial is an integral protein of the inner mitochondrial membrane. The enzyme couples hydride transfer of reducing equivalent between NAD(H) and NADP(+) to proton translocation across the inner mitochondrial membrane. Under most physiological conditions, the enzyme uses energy from the mitochondrial proton gradient to produce high concentrations of NADPH. The resulting NADPH is used for biosynthesis as well as in reactions inside the mitochondria required to remove reactive oxygen species such as to retain a reduced glutathione pool (high GSH/GSSG ratio). The enzyme may be inactivated by oxidative modifications.[10]
Reaction catalyzed:
NADPH + NAD+ = NADP+ + NADH.
Clinical significance
NAD(P) transhydrogenase, mitochondrial abundance may be associated with human heart failure.[11] In failing hearts, a partial loss of NAD(P) transhydrogenase's mitochondrial activity negatively impacts the NADPH-dependent enzyme activities in the mitochondria and the capacity of mitochondria to maintain proton gradients, which may adversely impact energy production and oxidative stress defense in heart failure and exacerbate oxidative damage to cellular proteins.[11]
Mutations in the NNT gene have been associated to familial glucocorticoid deficiency 1, a severe autosomal recessive disorder in human characterized by insensitivity to adrenocorticotropic hormone action on the adrenal cortex and an inability of the adrenal cortex to produce cortisol[12]Glucocorticoid deficiency 1 usually presents in neonatal to early childhood with episodes of hypoglycemia and other symptoms related to cortisol deficiency, including failure to thrive, recurrent illnesses or infections, convulsions, and shock. Diagnosis is confirmed with a low plasma cortisol measurement in the presence of an elevated adrenocorticotropic hormone level, and normal aldosterone and plasma renin measurements.[12]
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Arkblad EL, Helou K, Levan G, Rydström J (Sep 1997). "Mapping of the rat and mouse nicotinamide nucleotide transhydrogenase gene". Mammalian Genome. 8 (9): 703. doi:10.1007/s003359900546. PMID9271681. S2CID33003109.
↑ Zieger B, Ware J (May 1998). "Cloning and deduced amino acid sequence of human nicotinamide nucleotide transhydrogenase". DNA Sequence. 7 (6): 369–73. doi:10.3109/10425179709034058. PMID9524818.
Forsmark-Andrée P, Persson B, Radi R, Dallner G, Ernster L (Dec 1996). "Oxidative modification of nicotinamide nucleotide transhydrogenase in submitochondrial particles: effect of endogenous ubiquinol". Archives of Biochemistry and Biophysics. 336 (1): 113–20. doi:10.1006/abbi.1996.0538. PMID8951041.
Peake SJ, Jackson JB, White SA (Apr 2000). "The NADP(H)-binding component (dIII) of human heart transhydrogenase: crystallization and preliminary crystallographic analysis". Acta Crystallographica Section D. 56 (Pt 4): 489–91. Bibcode:2000AcCrD..56..489P. doi:10.1107/S0907444900001542. PMID10739929.
Arkblad EL, Egorov M, Shakhparonov M, Romanova L, Polzikov M, Rydström J (Sep 2002). "Expression of proton-pumping nicotinamide nucleotide transhydrogenase in mouse, human brain and C elegans". Comparative Biochemistry and Physiology B. 133 (1): 13–21. doi:10.1016/S1096-4959(02)00107-0. PMID12223207.
Taylor SW, Fahy E, Zhang B, Glenn GM, Warnock DE, Wiley S, Murphy AN, Gaucher SP, Capaldi RA, Gibson BW, Ghosh SS (Mar 2003). "Characterization of the human heart mitochondrial proteome". Nature Biotechnology. 21 (3): 281–6. doi:10.1038/nbt793. PMID12592411. S2CID27329521.
1d4o: CRYSTAL STRUCTURE OF TRANSHYDROGENASE DOMAIN III AT 1.2 ANGSTROMS RESOLUTION
1djl: THE CRYSTAL STRUCTURE OF HUMAN TRANSHYDROGENASE DOMAIN III WITH BOUND NADP
1pt9: Crystal Structure Analysis of the DIII Component of Transhydrogenase with a Thio-Nicotinamide Nucleotide Analogue
1u31: recombinant human heart transhydrogenase dIII bound with NADPH
This page is based on this Wikipedia article Text is available under the CC BY-SA 4.0 license; additional terms may apply. Images, videos and audio are available under their respective licenses.
