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'''L-2-hydroxyglutarate dehydrogenase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''L2HGDH'' [[gene]], also known as C14orf160,  on [[chromosome 14]].<ref name="pmid16005139">{{cite journal | vauthors = Rzem R, Van Schaftingen E, Veiga-da-Cunha M | title = The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase | journal = Biochimie | volume = 88 | issue = 1 | pages = 113–116 | date = Jan 2006 | pmid = 16005139 | pmc =  | doi = 10.1016/j.biochi.2005.06.005 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: L2HGDH L-2-hydroxyglutarate dehydrogenase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79944| accessdate = }}</ref>


== Function ==


'''L-2-hydroxyglutarate dehydrogenase''', also known as '''L2HGDH''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: L2HGDH L-2-hydroxyglutarate dehydrogenase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79944| accessdate = }}</ref>
This gene encodes L-2-hydroxyglutarate dehydrogenase, a [[flavin adenine dinucleotide]] (FAD)-dependent enzyme that oxidizes [[Alpha-Hydroxyglutaric acid|L-2-hydroxyglutarate]] to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause [[L-2-hydroxyglutaric aciduria]], a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.<ref name="entrez" />


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
L2HGDH codes for a protein that is 50 kDa in size. The L2HGDH protein contains a mitochondrial-targeting [[transit peptide]]<ref>http://www.uniprot.org/uniprot/Q9H9P8</ref> and is localized to the [[mitochondrial inner membrane]] inside [[mitochondria]] inside the cell. The L2HGDH protein catalyzes the following reaction,  and  requires [[flavin adenine dinucleotide]] (FAD) as a [[Cofactor (biochemistry)|co-factor]]:
{{PBB_Summary
| section_title =
| summary_text = This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause [[L-2-hydroxyglutaric aciduria]], a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.<ref name="entrez">{{cite web | title = Entrez Gene: L2HGDH L-2-hydroxyglutarate dehydrogenase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=79944| accessdate = }}</ref>
}}


==References==
(S)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.<ref name="pmid16005139"/>
{{reflist|2}}
 
==Further reading==
L-2-hydroxyglutarate is produced by [[Enzyme promiscuity|promiscuous action]] of [[malate dehydrogenase]] on 2-oxoglutarate; the L2HGDH protein is thus an example of a [[Metabolite damage and its repair or pre-emption|metabolite repair]] enzyme because it reconverts the useless damage product L-2-hydroxyglutarate back to 2-oxoglutarate.
{{refbegin | 2}}
 
{{PBB_Further_reading
== Clinical significance ==
| citations =
 
*{{cite journal | author=Duran M, Kamerling JP, Bakker HD, ''et al.'' |title=L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? |journal=J. Inherit. Metab. Dis. |volume=3 |issue= 4 |pages= 109–12 |year= 1981 |pmid= 6787330 |doi= }}
Mutations in the L2HGDH gene cause [[L-2-hydroxyglutaric aciduria]], a rare [[autosomal recessive]] neurometabolic disorder. Individuals with L2HGDH mutations present toxic accumulation of high concentration of [[L-2-hydroxyglutaric acid]] in the [[Blood plasma|plasma]] and [[cerebrospinal fluid]].<ref>{{cite journal | vauthors = Vilarinho L, Tafulo S, Sibilio M, Kok F, Fontana F, Diogo L, Venâncio M, Ferreira M, Nogueira C, Valongo C, Parenti G, Amorim A, Azevedo L | title = Identification of novel L2HGDH gene mutations and update of the pathological spectrum | journal = Journal of Human Genetics | volume = 55 | issue = 1 | pages = 55–8 | date = Jan 2010 | pmid = 19911013 | doi = 10.1038/jhg.2009.110 }}</ref> At least 70 disease-causing variants in the L2HGDH gene have been discovered in patients.<ref name="Steenweg 380–90">{{cite journal | vauthors = Steenweg ME, Jakobs C, Errami A, van Dooren SJ, Adeva Bartolomé MT, Aerssens P, Augoustides-Savvapoulou P, Baric I, Baumann M, Bonafé L, Chabrol B, Clarke JT, Clayton P, Coker M, Cooper S, Falik-Zaccai T, Gorman M, Hahn A, Hasanoglu A, King MD, de Klerk HB, Korman SH, Lee C, Meldgaard Lund A, Mejaski-Bosnjak V, Pascual-Castroviejo I, Raadhyaksha A, Rootwelt T, Roubertie A, Ruiz-Falco ML, Scalais E, Schimmel U, Seijo-Martinez M, Suri M, Sykut-Cegielska J, Trefz FK, Uziel G, Valayannopoulos V, Vianey-Saban C, Vlaho S, Vodopiutz J, Wajner M, Walter J, Walter-Derbort C, Yapici Z, Zafeiriou DI, Spreeuwenberg MD, Celli J, den Dunnen JT, van der Knaap MS, Salomons GS | title = An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study | journal = Human Mutation | volume = 31 | issue = 4 | pages = 380–90 | date = April 2010 | pmid = 20052767 | doi = 10.1002/humu.21197 | display-authors = 6}}</ref> Patients with [[L-2-hydroxyglutaric aciduria]] are associated with moderate to severe [[mental retardation]], [[psychomotor retardation]], [[cerebellar ataxia]], [[macrocephaly]], or [[epilepsy]].<ref name="Steenweg 380–90"/>
*{{cite journal | author=Jansen GA, Wanders RJ |title=L-2-hydroxyglutarate dehydrogenase: identification of a novel enzyme activity in rat and human liver. Implications for L-2-hydroxyglutaric acidemia. |journal=Biochim. Biophys. Acta |volume=1225 |issue= 1 |pages= 53–6 |year= 1993 |pmid= 8241290 |doi= }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
L2HGDH has a role in mediating differentiation in T-cells via its activity on S-2HG
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
<ref> {{cite journal | vauthors = Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Veliça P, You J, Chia GS, Sim J, Doedens A, Abelanet A, Evans CE, Griffiths JR, Poellinger L, Goldrath AW, Johnson RS | title = S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate| journal = Nature | volume = 540 | issue = 7632 | pages = 236–241 | date = Dec 2016 | pmid = 27798602 | doi = 10.1038/nature20165 }}</ref>
*{{cite journal | author=Topçu M, Jobard F, Halliez S, ''et al.'' |title=L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. |journal=Hum. Mol. Genet. |volume=13 |issue= 22 |pages= 2803–11 |year= 2006 |pmid= 15385440 |doi= 10.1093/hmg/ddh300 }}
 
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
== Molecular interactions ==
*{{cite journal | author=Rzem R, Veiga-da-Cunha M, Noël G, ''et al.'' |title=A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 48 |pages= 16849–54 |year= 2005 |pmid= 15548604 |doi= 10.1073/pnas.0404840101 }}
 
*{{cite journal | author=Rzem R, Van Schaftingen E, Veiga-da-Cunha M |title=The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. |journal=Biochimie |volume=88 |issue= 1 |pages= 113–6 |year= 2006 |pmid= 16005139 |doi= 10.1016/j.biochi.2005.06.005 }}
[[KLK10]]<ref>{{cite journal | vauthors = Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, Tam S, Zarraga G, Colby G, Baltier K, Dong R, Guarani V, Vaites LP, Ordureau A, Rad R, Erickson BK, Wühr M, Chick J, Zhai B, Kolippakkam D, Mintseris J, Obar RA, Harris T, Artavanis-Tsakonas S, Sowa ME, De Camilli P, Paulo JA, Harper JW, Gygi SP | title = The BioPlex Network: A Systematic Exploration of the Human Interactome | journal = Cell | volume = 162 | issue = 2 | pages = 425–40 | date = Jul 2015 | pmid = 26186194 | doi = 10.1016/j.cell.2015.06.043 | display-authors = 6 | pmc=4617211}}</ref>
*{{cite journal | author=Vilarinho L, Cardoso ML, Gaspar P, ''et al.'' |title=Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin. |journal=Hum. Mutat. |volume=26 |issue= 4 |pages= 395–6 |year= 2006 |pmid= 16134148 |doi= 10.1002/humu.9373 }}
 
*{{cite journal | author=Struys EA, Gibson KM, Jakobs C |title=Novel insights into L-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid. |journal=J. Inherit. Metab. Dis. |volume=30 |issue= 5 |pages= 690–3 |year= 2007 |pmid= 17876720 |doi= 10.1007/s10545-007-0697-5 }}
== See also ==
}}
* [[D2HGDH]]
* [[2-hydroxyglutarate synthase]]
* [[2-hydroxyglutarate dehydrogenase]]
* [[Hydroxyacid-oxoacid transhydrogenase]]
 
== References ==
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK | title = L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? | journal = Journal of Inherited Metabolic Disease | volume = 3 | issue = 4 | pages = 109–12 | year = 1981 | pmid = 6787330 | doi = 10.1007/BF02312543 }}
* {{cite journal | vauthors = Jansen GA, Wanders RJ | title = L-2-hydroxyglutarate dehydrogenase: identification of a novel enzyme activity in rat and human liver. Implications for L-2-hydroxyglutaric acidemia | journal = Biochimica et Biophysica Acta | volume = 1225 | issue = 1 | pages = 53–6 | date = Nov 1993 | pmid = 8241290 | doi = 10.1016/0925-4439(93)90121-g }}
* {{cite journal | vauthors = Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJ, Prud'homme JF, Lathrop M, Ozguc M, Fischer J | title = L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1 | journal = Human Molecular Genetics | volume = 13 | issue = 22 | pages = 2803–11 | date = Nov 2004 | pmid = 15385440 | doi = 10.1093/hmg/ddh300 }}
* {{cite journal | vauthors = Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E | title = A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 48 | pages = 16849–54 | date = Nov 2004 | pmid = 15548604 | pmc = 534725 | doi = 10.1073/pnas.0404840101 }}
* {{cite journal | vauthors = Vilarinho L, Cardoso ML, Gaspar P, Barbot C, Azevedo L, Diogo L, Santos M, Carrilho I, Fineza I, Kok F, Chorão R, Alegria P, Martins E, Teixeira J, Cabral Fernandes H, Verhoeven NM, Salomons GS, Santorelli FM, Cabral P, Amorim A, Jakobs C | title = Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin | journal = Human Mutation | volume = 26 | issue = 4 | pages = 395–6 | date = Oct 2005 | pmid = 16134148 | doi = 10.1002/humu.9373 }}
* {{cite journal | vauthors = Struys EA, Gibson KM, Jakobs C | title = Novel insights into L-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid | journal = Journal of Inherited Metabolic Disease | volume = 30 | issue = 5 | pages = 690–3 | date = Oct 2007 | pmid = 17876720 | doi = 10.1007/s10545-007-0697-5 }}
{{refend}}
{{refend}}


{{Alcohol oxidoreductases}}




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Revision as of 20:47, 28 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

L-2-hydroxyglutarate dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the L2HGDH gene, also known as C14orf160, on chromosome 14.[1][2]

Function

This gene encodes L-2-hydroxyglutarate dehydrogenase, a flavin adenine dinucleotide (FAD)-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.[2]

L2HGDH codes for a protein that is 50 kDa in size. The L2HGDH protein contains a mitochondrial-targeting transit peptide[3] and is localized to the mitochondrial inner membrane inside mitochondria inside the cell. The L2HGDH protein catalyzes the following reaction, and requires flavin adenine dinucleotide (FAD) as a co-factor:

(S)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.[1]

L-2-hydroxyglutarate is produced by promiscuous action of malate dehydrogenase on 2-oxoglutarate; the L2HGDH protein is thus an example of a metabolite repair enzyme because it reconverts the useless damage product L-2-hydroxyglutarate back to 2-oxoglutarate.

Clinical significance

Mutations in the L2HGDH gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder. Individuals with L2HGDH mutations present toxic accumulation of high concentration of L-2-hydroxyglutaric acid in the plasma and cerebrospinal fluid.[4] At least 70 disease-causing variants in the L2HGDH gene have been discovered in patients.[5] Patients with L-2-hydroxyglutaric aciduria are associated with moderate to severe mental retardation, psychomotor retardation, cerebellar ataxia, macrocephaly, or epilepsy.[5]

L2HGDH has a role in mediating differentiation in T-cells via its activity on S-2HG [6]

Molecular interactions

KLK10[7]

See also

References

  1. ↑ 1.0 1.1 Rzem R, Van Schaftingen E, Veiga-da-Cunha M (Jan 2006). "The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase". Biochimie. 88 (1): 113–116. doi:10.1016/j.biochi.2005.06.005. PMID 16005139.
  2. ↑ 2.0 2.1 "Entrez Gene: L2HGDH L-2-hydroxyglutarate dehydrogenase".
  3. ↑ http://www.uniprot.org/uniprot/Q9H9P8
  4. ↑ Vilarinho L, Tafulo S, Sibilio M, Kok F, Fontana F, Diogo L, Venâncio M, Ferreira M, Nogueira C, Valongo C, Parenti G, Amorim A, Azevedo L (Jan 2010). "Identification of novel L2HGDH gene mutations and update of the pathological spectrum". Journal of Human Genetics. 55 (1): 55–8. doi:10.1038/jhg.2009.110. PMID 19911013.
  5. ↑ 5.0 5.1 Steenweg ME, Jakobs C, Errami A, van Dooren SJ, Adeva Bartolomé MT, Aerssens P, et al. (April 2010). "An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study". Human Mutation. 31 (4): 380–90. doi:10.1002/humu.21197. PMID 20052767.
  6. ↑ Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT, Veliça P, You J, Chia GS, Sim J, Doedens A, Abelanet A, Evans CE, Griffiths JR, Poellinger L, Goldrath AW, Johnson RS (Dec 2016). "S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate". Nature. 540 (7632): 236–241. doi:10.1038/nature20165. PMID 27798602.
  7. ↑ Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, et al. (Jul 2015). "The BioPlex Network: A Systematic Exploration of the Human Interactome". Cell. 162 (2): 425–40. doi:10.1016/j.cell.2015.06.043. PMC 4617211. PMID 26186194.

Further reading

  • Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK (1981). "L-2-Hydroxyglutaric aciduria: an inborn error of metabolism?". Journal of Inherited Metabolic Disease. 3 (4): 109–12. doi:10.1007/BF02312543. PMID 6787330.
  • Jansen GA, Wanders RJ (Nov 1993). "L-2-hydroxyglutarate dehydrogenase: identification of a novel enzyme activity in rat and human liver. Implications for L-2-hydroxyglutaric acidemia". Biochimica et Biophysica Acta. 1225 (1): 53–6. doi:10.1016/0925-4439(93)90121-g. PMID 8241290.
  • Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJ, Prud'homme JF, Lathrop M, Ozguc M, Fischer J (Nov 2004). "L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1". Human Molecular Genetics. 13 (22): 2803–11. doi:10.1093/hmg/ddh300. PMID 15385440.
  • Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E (Nov 2004). "A gene encoding a putative FAD-dependent L-2-hydroxyglutarate dehydrogenase is mutated in L-2-hydroxyglutaric aciduria". Proceedings of the National Academy of Sciences of the United States of America. 101 (48): 16849–54. doi:10.1073/pnas.0404840101. PMC 534725. PMID 15548604.
  • Vilarinho L, Cardoso ML, Gaspar P, Barbot C, Azevedo L, Diogo L, Santos M, Carrilho I, Fineza I, Kok F, Chorão R, Alegria P, Martins E, Teixeira J, Cabral Fernandes H, Verhoeven NM, Salomons GS, Santorelli FM, Cabral P, Amorim A, Jakobs C (Oct 2005). "Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin". Human Mutation. 26 (4): 395–6. doi:10.1002/humu.9373. PMID 16134148.
  • Struys EA, Gibson KM, Jakobs C (Oct 2007). "Novel insights into L-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid". Journal of Inherited Metabolic Disease. 30 (5): 690–3. doi:10.1007/s10545-007-0697-5. PMID 17876720.


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