L2HGDH explained

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.

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

• D2HGDH
• 2-hydroxyglutarate synthase
• 2-hydroxyglutarate dehydrogenase
• Hydroxyacid-oxoacid transhydrogenase

Further reading

• Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK . L-2-Hydroxyglutaric aciduria: an inborn error of metabolism? . Journal of Inherited Metabolic Disease . 3 . 4 . 109–12 . 1981 . 6787330 . 10.1007/BF02312543 . 22073735 .
• Jansen GA, Wanders RJ . 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 (BBA) - Molecular Basis of Disease . 1225 . 1 . 53–6 . Nov 1993 . 8241290 . 10.1016/0925-4439(93)90121-g .
• Topçu M, Jobard F, Halliez S, Coskun T, Yalçinkayal C, Gerceker FO, Wanders RJ, Prud'homme JF, Lathrop M, Ozguc M, Fischer J . L-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1 . Human Molecular Genetics . 13 . 22 . 2803–11 . Nov 2004 . 15385440 . 10.1093/hmg/ddh300 . free .
• Rzem R, Veiga-da-Cunha M, Noël G, Goffette S, Nassogne MC, Tabarki B, Schöller C, Marquardt T, Vikkula M, Van Schaftingen E . 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 . Nov 2004 . 15548604 . 534725 . 10.1073/pnas.0404840101 . 2004PNAS..10116849R . free .
• 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 . Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin . Human Mutation . 26 . 4 . 395–6 . Oct 2005 . 16134148 . 10.1002/humu.9373 . free .
• Struys EA, Gibson KM, Jakobs C . 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 . Oct 2007 . 17876720 . 10.1007/s10545-007-0697-5 . 10571813 .

Notes and References

1. Rzem R, Van Schaftingen E, Veiga-da-Cunha M . The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase . Biochimie . 88 . 1 . 113–116 . Jan 2006 . 16005139 . 10.1016/j.biochi.2005.06.005 .
2. Web site: Entrez Gene: L2HGDH L-2-hydroxyglutarate dehydrogenase.
3. Web site: L2HGDH - L-2-hydroxyglutarate dehydrogenase, mitochondrial precursor - Homo sapiens (Human) - L2HGDH gene & protein. www.uniprot.org.
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 . Identification of novel L2HGDH gene mutations and update of the pathological spectrum . Journal of Human Genetics . 55 . 1 . 55–8 . Jan 2010 . 19911013 . 10.1038/jhg.2009.110 . free .
5. 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 . An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype-phenotype study . Human Mutation . 31 . 4 . 380–90 . April 2010 . 20052767 . 10.1002/humu.21197 . 6. free .
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 . S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature . 540 . 7632 . 236–241 . Dec 2016 . 27798602 . 10.1038/nature20165 . 5149074. 2016Natur.540..236T.
7. 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 . The BioPlex Network: A Systematic Exploration of the Human Interactome . Cell . 162 . 2 . 425–40 . Jul 2015 . 26186194 . 10.1016/j.cell.2015.06.043 . 6 . 4617211.