NNT (gene)

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NNT
Protein NNT PDB 1d4o.png
Available structures
PDBHuman UniProt search: PDBe RCSB
Identifiers
AliasesNNT, GCCD4, nicotinamide nucleotide transhydrogenase
External IDsHomoloGene: 7445 GeneCards: NNT
Gene location (Human)
Chromosome 5 (human)
Chr.Chromosome 5 (human)[1]
Chromosome 5 (human)
Genomic location for NNT
Genomic location for NNT
Band5p12Start43,602,692 bp[1]
End43,707,405 bp[1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_012343
NM_182977
NM_001331026

n/a

RefSeq (protein)

NP_001317955
NP_036475
NP_892022

n/a

Location (UCSC)Chr 5: 43.6 – 43.71 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

NAD(P) transhydrogenase, mitochondrial is an enzyme that in humans is encoded by the NNT gene on chromosome 5.[3][4][5]

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.[5]

Structure[edit]

Transhydrogenases including NNT can exist in an ‘open’ conformation,[6] 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.[6] The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane.[7] 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.[7]

Function[edit]

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.[8]

Reaction catalyzed:

  • NADPH + NAD+ = NADP+ + NADH.

Clinical significance[edit]

NAD(P) transhydrogenase, mitochondrial abundance may be associated with human heart failure.[9] 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.[9]

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 [10] 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.[10]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000112992 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:".
  3. ^ 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. PMID 9271681.
  4. ^ 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. PMID 9524818.
  5. ^ a b "Entrez Gene: NNT nicotinamide nucleotide transhydrogenase".
  6. ^ a b Jackson JB (2003). "Proton translocation by transhydrogenase". FEBS Lett. 545 (1): 18–24. doi:10.1016/s0014-5793(03)00388-0. PMID 12788487.
  7. ^ a b White SA, Peake SJ, McSweeney S, Leonard G, Cotton NP, Jackson JB (2000). "The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria". Structure. 8 (1): 1–12. doi:10.1016/s0969-2126(00)00075-7. PMID 10673423.
  8. ^ Forsmark-Andrée P, Persson B, Radi R, Dallner G, Ernster L (1996). "Oxidative modification of nicotinamide nucleotide transhydrogenase in submitochondrial particles: effect of endogenous ubiquinol". Arch. Biochem. Biophys. 336 (1): 113–20. doi:10.1006/abbi.1996.0538. PMID 8951041.
  9. ^ a b Sheeran FL, Rydström J, Shakhparonov MI, Pestov NB, Pepe S (2010). "Diminished NADPH transhydrogenase activity and mitochondrial redox regulation in human failing myocardium". Biochim. Biophys. Acta. 1797 (6–7): 1138–48. doi:10.1016/j.bbabio.2010.04.002. PMID 20388492.
  10. ^ a b Meimaridou E, Kowalczyk J, Guasti L, Hughes CR, Wagner F, Frommolt P, Nürnberg P, Mann NP, Banerjee R, Saka HN, Chapple JP, King PJ, Clark AJ, Metherell LA (Jul 2012). "Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency". Nature Genetics. 44 (7): 740–2. doi:10.1038/ng.2299. PMC 3386896. PMID 22634753.

Further reading[edit]