NNT (gene): Difference between revisions
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'''NAD(P) transhydrogenase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''NNT'' [[gene]] on chromosome 5.<ref name="pmid9271681">{{cite journal | vauthors = Arkblad EL, Helou K, Levan G, Rydström J | title = Mapping of the rat and mouse nicotinamide nucleotide transhydrogenase gene | journal = Mammalian Genome | volume = 8 | issue = 9 | pages = 703 | date = Sep 1997 | pmid = 9271681 | pmc = | doi = 10.1007/s003359900546 }}</ref><ref name="pmid9524818">{{cite journal | vauthors = Zieger B, Ware J | title = Cloning and deduced amino acid sequence of human nicotinamide nucleotide transhydrogenase | journal = DNA Sequence | volume = 7 | issue = 6 | pages = 369–73 | date = May 1998 | pmid = 9524818 | pmc = | doi = 10.3109/10425179709034058 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NNT nicotinamide nucleotide transhydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23530| accessdate = }}</ref> | '''NAD(P) transhydrogenase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''NNT'' [[gene]] on chromosome 5.<ref name="pmid9271681">{{cite journal | vauthors = Arkblad EL, Helou K, Levan G, Rydström J | title = Mapping of the rat and mouse nicotinamide nucleotide transhydrogenase gene | journal = Mammalian Genome | volume = 8 | issue = 9 | pages = 703 | date = Sep 1997 | pmid = 9271681 | pmc = | doi = 10.1007/s003359900546 }}</ref><ref name="pmid9524818">{{cite journal | vauthors = Zieger B, Ware J | title = Cloning and deduced amino acid sequence of human nicotinamide nucleotide transhydrogenase | journal = DNA Sequence | volume = 7 | issue = 6 | pages = 369–73 | date = May 1998 | pmid = 9524818 | pmc = | doi = 10.3109/10425179709034058 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NNT nicotinamide nucleotide transhydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23530| accessdate = }}</ref> | ||
The NNT gene contains 26 exons and encodes a [[transhydrogenase]] | 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.<ref name="entrez"/> | ||
== Structure == | == Structure == | ||
Transhydrogenases including NNT can exist in an ‘open’ conformation,<ref name = "Jackson_2003">{{cite journal |vauthors=Jackson JB |title=Proton translocation by transhydrogenase |journal=FEBS Lett. |volume=545 |issue=1 |pages=18–24 |year=2003 |pmid=12788487 |doi= 10.1016/s0014-5793(03)00388-0|url=}}</ref> 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 | Transhydrogenases including NNT can exist in an ‘open’ conformation,<ref name = "Jackson_2003">{{cite journal |vauthors=Jackson JB |title=Proton translocation by transhydrogenase |journal=FEBS Lett. |volume=545 |issue=1 |pages=18–24 |year=2003 |pmid=12788487 |doi= 10.1016/s0014-5793(03)00388-0|url=}}</ref> 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.<ref name = "Jackson_2003"/> The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane.<ref name="ReferenceA">{{cite journal |vauthors=White SA, Peake SJ, McSweeney S, Leonard G, Cotton NP, Jackson JB |title=The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria |journal=Structure |volume=8 |issue=1 |pages=1–12 |year=2000 |pmid=10673423 |doi= 10.1016/s0969-2126(00)00075-7|url=}}</ref> 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 {{not a typo|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.<ref name="ReferenceA"/> | ||
== Function == | == Function == | ||
Latest revision as of 03:01, 20 August 2018
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NAD(P) transhydrogenase, mitochondrial is an enzyme that in humans is encoded by the NNT gene on chromosome 5.[1][2][3]
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.[3]
Structure
Transhydrogenases including NNT can exist in an ‘open’ conformation,[4] 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.[4] The protein comprises three subunits (dI, dII and dIII), with the dII component spanning the inner mitochondrial membrane.[5] 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.[5]
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.[6]
Reaction catalyzed:
- NADPH + NAD+ = NADP+ + NADH.
Clinical significance
NAD(P) transhydrogenase, mitochondrial abundance may be associated with human heart failure.[7] 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.[7]
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 [8] 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.[8]
References
- ↑ 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.
- ↑ 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.
- ↑ 3.0 3.1 "Entrez Gene: NNT nicotinamide nucleotide transhydrogenase".
- ↑ 4.0 4.1 Jackson JB (2003). "Proton translocation by transhydrogenase". FEBS Lett. 545 (1): 18–24. doi:10.1016/s0014-5793(03)00388-0. PMID 12788487.
- ↑ 5.0 5.1 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.
- ↑ 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.
- ↑ 7.0 7.1 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.
- ↑ 8.0 8.1 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
- Jackson JB (Jun 2003). "Proton translocation by transhydrogenase". FEBS Letters. 545 (1): 18–24. doi:10.1016/S0014-5793(03)00388-0. PMID 12788487.
- 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. 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. 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.
- 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.
