NNT (gene)

NNT
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1DJL, 1PT9, 1U31
Identifiers
Aliases	NNT, GCCD4, nicotinamide nucleotide transhydrogenase
External IDs	OMIM: 607878; MGI: 109279; HomoloGene: 7445; GeneCards: NNT; OMA:NNT - orthologs
Gene location (Human) Chr. Chromosome 5 (human) Band 5p12 Start 43,602,692 bp End 43,707,405 bp
Gene location (Mouse) Chr. Chromosome 13 (mouse) Band 13 D2.3|13 67.21 cM Start 119,471,984 bp End 119,545,533 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right ventricle muscle of thigh biceps brachii thoracic diaphragm left ventricle right auricle Skeletal muscle tissue of biceps brachii Skeletal muscle tissue of rectus abdominis gastrocnemius muscle vastus lateralis muscle Top expressed in right kidney granulocyte muscle of thigh tail of embryo ventricular zone genital tubercle yolk sac urethra embryo neural tube More reference expression data BioGPS n/a
Gene ontology Molecular function oxidoreductase activity NAD binding NAD(P)+ transhydrogenase (AB-specific) activity NAD(P)+ transhydrogenase (B-specific) activity NAD(P)+ transhydrogenase activity NADP binding Cellular component integral component of membrane mitochondrial inner membrane membrane mitochondrion mitochondrial respirasome Biological process reactive oxygen species metabolic process tricarboxylic acid cycle NADPH regeneration proton transmembrane transport negative regulation of protein phosphorylation positive regulation of mitochondrial membrane potential oxygen homeostasis response to vitamin negative regulation of apoptotic process cell redox homeostasis cellular oxidant detoxification positive regulation of hydrogen peroxide catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23530 18115 Ensembl ENSG00000112992 ENSMUSG00000025453 UniProt Q13423 Q61941 RefSeq (mRNA) NM_012343 NM_182977 NM_001331026 NM_008710 NM_001308506 RefSeq (protein) NP_001317955 NP_036475 NP_892022 n/a Location (UCSC) Chr 5: 43.6 – 43.71 Mb Chr 13: 119.47 – 119.55 Mb PubMed search
Wikidata
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NAD(P) transhydrogenase, mitochondrial is an enzyme that in humans is encoded by the NNT gene on chromosome 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.

Structure

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

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.

Reaction catalyzed:

• NADPH + NAD+ = NADP+ + NADH.

Clinical significance

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

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 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.

Further reading

• Jackson JB (Jun 2003). "Proton translocation by transhydrogenase". FEBS Letters. 545 (1): 18–24. doi:10.1016/S0014-5793(03)00388-0. PMID 12788487. S2CID 29235071.
• Arkblad EL, Betsholtz C, Rydström J (Mar 1996). "The cDNA sequence of proton-pumping nicotinamide nucleotide transhydrogenase from man and mouse". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1273 (3): 203–5. doi:10.1016/0005-2728(95)00159-X. PMID 8616157.
• 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. PMID 8951041.
• White SA, Peake SJ, McSweeney S, Leonard G, Cotton NP, Jackson JB (Jan 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.
• 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. PMID 10739929.
• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
• Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
• 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. PMID 12223207.
• 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. PMID 12592411. S2CID 27329521.
• Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (Jan 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
• Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.