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{{Infobox_gene}}
{{Infobox_gene}}
'''Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial''' (SUCLA2), also known as  ADP-forming succinyl-CoA synthetase (SCS-A), is an [[enzyme]] that in humans is encoded by the ''SUCLA2'' [[gene]] on chromosome 13.<ref name="pmid9765291">{{cite journal | vauthors = Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO | title = Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes | journal = The Journal of Biological Chemistry | volume = 273 | issue = 42 | pages = 27580–6 | date = Oct 1998 | pmid = 9765291 | pmc =  | doi = 10.1074/jbc.273.42.27580 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SUCLA2 succinate-CoA ligase, ADP-forming, beta subunit| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8803| accessdate = }}</ref><ref name=pmid24986829>{{cite journal|last1=Matilainen|first1=S|last2=Isohanni|first2=P|last3=Euro|first3=L|last4=Lönnqvist|first4=T|last5=Pihko|first5=H|last6=Kivelä|first6=T|last7=Knuutila|first7=S|last8=Suomalainen|first8=A|title=Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion.|journal=European Journal of Human Genetics|date=March 2015|volume=23|issue=3|pages=325–30|pmid=24986829|doi=10.1038/ejhg.2014.128|pmc=4326715}}</ref>
'''Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial''' (SUCLA2), also known as  ADP-forming succinyl-CoA synthetase (SCS-A), is an [[enzyme]] that in humans is encoded by the ''SUCLA2'' [[gene]] on chromosome 13.<ref name="pmid9765291">{{cite journal | vauthors = Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO | title = Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes | journal = The Journal of Biological Chemistry | volume = 273 | issue = 42 | pages = 27580–6 | date = October 1998 | pmid = 9765291 | pmc =  | doi = 10.1074/jbc.273.42.27580 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: SUCLA2 succinate-CoA ligase, ADP-forming, beta subunit| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8803| accessdate = }}</ref><ref name=pmid24986829>{{cite journal | vauthors = Matilainen S, Isohanni P, Euro L, Lönnqvist T, Pihko H, Kivelä T, Knuutila S, Suomalainen A | title = Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion | journal = European Journal of Human Genetics | volume = 23 | issue = 3 | pages = 325–30 | date = March 2015 | pmid = 24986829 | pmc = 4326715 | doi = 10.1038/ejhg.2014.128 }}</ref>


[[Succinyl-CoA synthetase]] (SCS) is a [[mitochondrial matrix]] enzyme that acts as a [[heterodimer]], being composed of an invariant alpha [[protein subunit|subunit]] and a [[substrate (chemistry)|substrate]]-specific beta subunit. The protein encoded by this gene is an [[Adenosine triphosphate|ATP]]-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the [[tricarboxylic acid cycle]]. SCS-A [[hydrolyze]]s ATP to convert [[succinate]] to [[succinyl-CoA]]. Defects in this gene are a cause of [[myopathic]] [[mitochondrial DNA depletion syndrome]]. A [[pseudogene]] of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]<ref name="entrez"/>
[[Succinyl-CoA synthetase]] (SCS) is a [[mitochondrial matrix]] enzyme that acts as a [[heterodimer]], being composed of an invariant alpha [[protein subunit|subunit]] and a [[substrate (chemistry)|substrate]]-specific beta subunit. The protein encoded by this gene is an [[Adenosine triphosphate|ATP]]-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the [[tricarboxylic acid cycle]]. SCS-A [[hydrolyze]]s ATP to convert [[succinyl-CoA]] to [[succinate]]. Defects in this gene are a cause of [[myopathic]] [[mitochondrial DNA depletion syndrome]]. A [[pseudogene]] of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]<ref name="entrez"/>


== Structure ==
== Structure ==
SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the ''[[SUCLG1]]'' gene and a β subunit encoded by either the ''SUCLA2'' gene or the ''[[SUCLG2]]'' gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the ''SUCLA2''-encoded β subunit.<ref name=pmid21295139>{{cite journal|last1=Miller|first1=C|last2=Wang|first2=L|last3=Ostergaard|first3=E|last4=Dan|first4=P|last5=Saada|first5=A|title=The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion.|journal=Biochimica et Biophysica Acta|date=May 2011|volume=1812|issue=5|pages=625–9|pmid=21295139|doi=10.1016/j.bbadis.2011.01.013}}</ref><ref name=pmid25370487>{{cite journal|last1=Dobolyi|first1=A|last2=Bagó|first2=AG|last3=Gál|first3=A|last4=Molnár|first4=MJ|last5=Palkovits|first5=M|last6=Adam-Vizi|first6=V|last7=Chinopoulos|first7=C|title=Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain.|journal=Journal of bioenergetics and biomembranes|date=April 2015|volume=47|issue=1-2|pages=33–41|pmid=25370487|doi=10.1007/s10863-014-9586-4}}</ref><ref name=pmid24085565>{{cite journal|last1=Dobolyi|first1=A|last2=Ostergaard|first2=E|last3=Bagó|first3=AG|last4=Dóczi|first4=T|last5=Palkovits|first5=M|last6=Gál|first6=A|last7=Molnár|first7=MJ|last8=Adam-Vizi|first8=V|last9=Chinopoulos|first9=C|title=Exclusive neuronal expression of SUCLA2 in the human brain.|journal=Brain structure & function|date=January 2015|volume=220|issue=1|pages=135–51|pmid=24085565|doi=10.1007/s00429-013-0643-2}}</ref> [[Amino acid]] sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.<ref name=pmid9765291/>
SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the ''[[SUCLG1]]'' gene and a β subunit encoded by either the ''SUCLA2'' gene or the ''[[SUCLG2]]'' gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the ''SUCLA2''-encoded β subunit.<ref name=pmid21295139>{{cite journal | vauthors = Miller C, Wang L, Ostergaard E, Dan P, Saada A | title = The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion | journal = Biochimica et Biophysica Acta | volume = 1812 | issue = 5 | pages = 625–9 | date = May 2011 | pmid = 21295139 | doi = 10.1016/j.bbadis.2011.01.013 }}</ref><ref name=pmid25370487>{{cite journal | vauthors = Dobolyi A, Bagó AG, Gál A, Molnár MJ, Palkovits M, Adam-Vizi V, Chinopoulos C | title = Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain | journal = Journal of Bioenergetics and Biomembranes | volume = 47 | issue = 1-2 | pages = 33–41 | date = April 2015 | pmid = 25370487 | doi = 10.1007/s10863-014-9586-4 }}</ref><ref name=pmid24085565>{{cite journal | vauthors = Dobolyi A, Ostergaard E, Bagó AG, Dóczi T, Palkovits M, Gál A, Molnár MJ, Adam-Vizi V, Chinopoulos C | title = Exclusive neuronal expression of SUCLA2 in the human brain | journal = Brain Structure & Function | volume = 220 | issue = 1 | pages = 135–51 | date = January 2015 | pmid = 24085565 | doi = 10.1007/s00429-013-0643-2 }}</ref> [[Amino acid]] sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.<ref name=pmid9765291/>


''SUCLA2'' is located on chromosome 13 and contains 13 [[exon]]s.<ref name="entrez"/>
''SUCLA2'' is located on chromosome 13 and contains 13 [[exon]]s.<ref name="entrez"/>
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== Clinical significance ==
== Clinical significance ==


Mutations in the SUCLA2 gene are associated with [[mitochondrial DNA depletion syndrome|mitochondrial DNA (mtDNA) depletion syndrome]].<ref name = "Ostergaard_2009">{{cite journal | title = SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Acuduria | vauthors = Ostergaard E | veditors = Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K | journal = GeneReviews [Internet] | location = Seattle (WA) | publisher = University of Washington, Seattle | year = May 2009 | url = https://www.ncbi.nlm.nih.gov/books/NBK6803/ | department = review }}</ref><ref name="El-Hattab_2013">{{cite journal | vauthors = El-Hattab AW, Scaglia F | title = Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options | journal = Neurotherapeutics | volume = 10 | issue = 2 | pages = 186–98 | year = 2013 | pmid = 23385875 | pmc = 3625391 | doi = 10.1007/s13311-013-0177-6 | department = review }}</ref> Symptoms include early onset [[hypotonia|low muscle tone]], severe muscular atrophy, [[scoliosis]], movement disorders such as [[dystonia]] and [[hyperkinesia]], [[epilepsy]], and growth retardation. There currently is no curative therapy. Treatment is restricted to managing symptoms and includes exercises to promote mobility, respiratory assistance, [[baclofen]] to treat [[dystonia]] and [[hyperkinesia]], and antiepileptic drugs for seizures.<ref name = "Ostergaard_2009"/><ref name="Parikh_2009">{{cite journal | vauthors = Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM | title = A modern approach to the treatment of mitochondrial disease | journal = Current Treatment Options in Neurology | volume = 11 | issue = 6 | pages = 414–30 | date = Nov 2009 | pmid = 19891905 | pmc = 3561461 | doi = 10.1007/s11940-009-0046-0| department = primary source}}</ref>
Mutations in the SUCLA2 gene are associated with [[mitochondrial DNA depletion syndrome|mitochondrial DNA (mtDNA) depletion syndrome]].<ref name = "Ostergaard_2009">{{cite journal | title = SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Acuduria | vauthors = Ostergaard E | veditors = Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K | journal = GeneReviews [Internet] | location = Seattle (WA) | publisher = University of Washington, Seattle | year = May 2009 | url = https://www.ncbi.nlm.nih.gov/books/NBK6803/ | department = review }}</ref><ref name="El-Hattab_2013">{{cite journal | vauthors = El-Hattab AW, Scaglia F | title = Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options | journal = Neurotherapeutics | volume = 10 | issue = 2 | pages = 186–98 | date = April 2013 | pmid = 23385875 | pmc = 3625391 | doi = 10.1007/s13311-013-0177-6 | department = review }}</ref> Symptoms include early onset [[hypotonia|low muscle tone]], severe muscular atrophy, [[scoliosis]], movement disorders such as [[dystonia]] and [[hyperkinesia]], [[epilepsy]], and growth retardation. Because succinic acid can not be made from succinyl coa, treatment is with oral succinic acid, which allows the krebs cycle, and electron transport chain to function correctly. Other treatments are managing symptoms and includes exercises to promote mobility, respiratory assistance, [[baclofen]] to treat [[dystonia]] and [[hyperkinesia]], and antiepileptic drugs for seizures.<ref name = "Ostergaard_2009"/><ref name="Parikh_2009">{{cite journal | vauthors = Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM | title = A modern approach to the treatment of mitochondrial disease | journal = Current Treatment Options in Neurology | volume = 11 | issue = 6 | pages = 414–30 | date = November 2009 | pmid = 19891905 | pmc = 3561461 | doi = 10.1007/s11940-009-0046-0 | department = primary source }}</ref>


There is a relatively high incidence of a specific SUCLA2 mutation in the [[Faroe Islands]] due to a [[founder effect]].  This particular mutation is often associated with early lethality.<ref name="Ostergaard_2007">{{cite journal | vauthors = Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M | title = Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations | journal = Brain | volume = 130 | issue = Pt 3 | pages = 853–61 | date = Mar 2007 | pmid = 17287286 | doi = 10.1093/brain/awl383 | department = primary source }}</ref>  Two additional  founder mutations in have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.<ref name="Carrozzo_2015">{{cite journal | vauthors = Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E | display-authors = 6 | title = Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients | journal = Journal of Inherited Metabolic Disease | volume = 39| issue = | date = Oct 2015 | pmid = 26475597 | doi = 10.1007/s10545-015-9894-9 | department = primary source | pages=243–52}}</ref> These patients show a higher variability in outcomes with a number of patients with SUCLA2 [[missense mutation]] surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.<ref name="Carrozzo_2015"/>
There is a relatively high incidence of a specific SUCLA2 mutation in the [[Faroe Islands]] due to a [[founder effect]].  This particular mutation is often associated with early lethality.<ref name="Ostergaard_2007">{{cite journal | vauthors = Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M | title = Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations | journal = Brain | volume = 130 | issue = Pt 3 | pages = 853–61 | date = March 2007 | pmid = 17287286 | doi = 10.1093/brain/awl383 | department = primary source }}</ref>  Two additional  founder mutations in have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.<ref name="Carrozzo_2015">{{cite journal | vauthors = Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E | title = Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients | journal = Journal of Inherited Metabolic Disease | volume = 39 | issue = 2 | pages = 243–52 | date = March 2016 | pmid = 26475597 | doi = 10.1007/s10545-015-9894-9 | department = primary source }}</ref> These patients show a higher variability in outcomes with a number of patients with SUCLA2 [[missense mutation]] surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.<ref name="Carrozzo_2015"/>


[[Coenzyme Q10]] and antioxidants have been used to treat mitochondrial DNA depletion syndrome but there is currently no evidence that these treatments result in clinical benefit.<ref name="Parikh_2009"/><ref name="pmid22513923">{{cite journal | vauthors = Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF | title = Treatment for mitochondrial disorders | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = | pages = CD004426 | year = 2012 | pmid = 22513923 | doi = 10.1002/14651858.CD004426.pub3 | department = review }}</ref>
[[Coenzyme Q10]] and antioxidants have been used to treat mitochondrial DNA depletion syndrome but there is currently no evidence that these treatments result in clinical benefit.<ref name="Parikh_2009"/><ref name="pmid22513923">{{cite journal | vauthors = Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF | title = Treatment for mitochondrial disorders | journal = The Cochrane Database of Systematic Reviews | volume = 4 | issue = 4 | pages = CD004426 | date = April 2012 | pmid = 22513923 | doi = 10.1002/14651858.CD004426.pub3 | department = review }}</ref>


Mutations in the ''SUCLA2'' gene leading to SUCLA2 deficiency result in [[Leigh's syndrome|Leigh's]] or a Leigh-like syndrome with onset of severe [[hypotonia]], [[muscular atrophy]], sensorineural hearing impairment, and often death in early childhood.<ref name=pmid21295139/><ref name=pmid24085565/>
Mutations in the ''SUCLA2'' gene leading to SUCLA2 deficiency result in [[Leigh's syndrome|Leigh's]] or a Leigh-like syndrome with onset of severe [[hypotonia]], [[muscular atrophy]], sensorineural hearing impairment, and often death in early childhood.<ref name=pmid21295139/><ref name=pmid24085565/>
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== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1-2 | pages = 171–4 | date = January 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1-2 | pages = 149–56 | date = October 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
* {{cite journal | vauthors = Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ | title = Antigens recognized by autologous antibody in patients with renal-cell carcinoma | journal = International Journal of Cancer | volume = 83 | issue = 4 | pages = 456–64 | date = Nov 1999 | pmid = 10508479 | doi = 10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5 }}
* {{cite journal | vauthors = Scanlan MJ, Gordan JD, Williamson B, Stockert E, Bander NH, Jongeneel V, Gure AO, Jäger D, Jäger E, Knuth A, Chen YT, Old LJ | title = Antigens recognized by autologous antibody in patients with renal-cell carcinoma | journal = International Journal of Cancer | volume = 83 | issue = 4 | pages = 456–64 | date = November 1999 | pmid = 10508479 | doi = 10.1002/(SICI)1097-0215(19991112)83:4<456::AID-IJC4>3.0.CO;2-5 }}
* {{cite journal | vauthors = Furuyama K, Sassa S | title = Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia | journal = The Journal of Clinical Investigation | volume = 105 | issue = 6 | pages = 757–64 | date = Mar 2000 | pmid = 10727444 | pmc = 377455 | doi = 10.1172/JCI6816 }}
* {{cite journal | vauthors = Furuyama K, Sassa S | title = Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia | journal = The Journal of Clinical Investigation | volume = 105 | issue = 6 | pages = 757–64 | date = March 2000 | pmid = 10727444 | pmc = 377455 | doi = 10.1172/JCI6816 }}
* {{cite journal | vauthors = Cox TC, Sadlon TJ, Schwarz QP, Matthews CS, Wise PD, Cox LL, Bottomley SS, May BK | title = The major splice variant of human 5-aminolevulinate synthase-2 contributes significantly to erythroid heme biosynthesis | journal = The International Journal of Biochemistry & Cell Biology | volume = 36 | issue = 2 | pages = 281–95 | date = Feb 2004 | pmid = 14643893 | doi = 10.1016/S1357-2725(03)00246-2 }}
* {{cite journal | vauthors = Cox TC, Sadlon TJ, Schwarz QP, Matthews CS, Wise PD, Cox LL, Bottomley SS, May BK | title = The major splice variant of human 5-aminolevulinate synthase-2 contributes significantly to erythroid heme biosynthesis | journal = The International Journal of Biochemistry & Cell Biology | volume = 36 | issue = 2 | pages = 281–95 | date = February 2004 | pmid = 14643893 | doi = 10.1016/S1357-2725(03)00246-2 }}
* {{cite journal | vauthors = Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ | title = Immunoaffinity profiling of tyrosine phosphorylation in cancer cells | journal = Nature Biotechnology | volume = 23 | issue = 1 | pages = 94–101 | date = Jan 2005 | pmid = 15592455 | doi = 10.1038/nbt1046 }}
* {{cite journal | vauthors = Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ | title = Immunoaffinity profiling of tyrosine phosphorylation in cancer cells | journal = Nature Biotechnology | volume = 23 | issue = 1 | pages = 94–101 | date = January 2005 | pmid = 15592455 | doi = 10.1038/nbt1046 }}
* {{cite journal | vauthors = Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A | title = Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion | journal = American Journal of Human Genetics | volume = 76 | issue = 6 | pages = 1081–6 | date = Jun 2005 | pmid = 15877282 | pmc = 1196446 | doi = 10.1086/430843 }}
* {{cite journal | vauthors = Elpeleg O, Miller C, Hershkovitz E, Bitner-Glindzicz M, Bondi-Rubinstein G, Rahman S, Pagnamenta A, Eshhar S, Saada A | title = Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion | journal = American Journal of Human Genetics | volume = 76 | issue = 6 | pages = 1081–6 | date = June 2005 | pmid = 15877282 | pmc = 1196446 | doi = 10.1086/430843 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}
{{refend}}
{{refend}}


== External links ==
== External links ==
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sucla2-def  GeneReview/NCBI/NIH/UW entry on SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria]
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=sucla2-def  GeneReview/NCBI/NIH/UW entry on SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Aciduria]

Revision as of 04:58, 9 December 2017

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Orthologs
SpeciesHumanMouse
Entrez

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RefSeq (mRNA)

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RefSeq (protein)

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Succinyl-CoA ligase [ADP-forming] subunit beta, mitochondrial (SUCLA2), also known as ADP-forming succinyl-CoA synthetase (SCS-A), is an enzyme that in humans is encoded by the SUCLA2 gene on chromosome 13.[1][2][3]

Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinyl-CoA to succinate. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008][2]

Structure

SCS, also known as succinyl CoA ligase (SUCL), is a heterodimer composed of a catalytic α subunit encoded by the SUCLG1 gene and a β subunit encoded by either the SUCLA2 gene or the SUCLG2 gene, which determines the enzyme specificity for either ADP or GDP. SUCLA2 is the SCS variant containing the SUCLA2-encoded β subunit.[4][5][6] Amino acid sequence alignment of the two β subunit types reveals a homology of ~50% identity, with specific regions conserved throughout the sequences.[1]

SUCLA2 is located on chromosome 13 and contains 13 exons.[2]

Function

As a subunit of SCS, SUCLA2 is a mitochondrial matrix enzyme that catalyzes the reversible conversion of succinyl-CoA to succinate and acetoacetyl CoA, accompanied by the substrate-level phosphorylation of ADP to ATP, as a step in the tricarboxylic acid (TCA) cycle.[4][5][6] The ATP generated is then consumed in catabolic pathways.[5] Since substrate-level phosphorylation does not require oxygen for ATP production, this reaction can rescue cells from cytosolic ATP depletion during ischemia.[6] The reverse reaction generates succinyl-CoA from succinate to fuel ketone body and heme synthesis.[4][6]

While SCS is ubiquitously expressed, SUCLA2 is predominantly expressed in catabolic tissues reliant on ATP as their main energy source, including heart, brain, and skeletal muscle.[1][3][6] Within the brain, SUCLA2 is found exclusively in neurons; meanwhile, both SUCLA2 and SUCLG2 are absent in astrocytes, microglia, and oligodendrocytes. In order to acquire succinate to continue the TCA cycle, these cells may instead synthesize succinate through GABA metabolism of α-ketoglutarate or ketone body metabolism of succinyl-CoA.[5][6]

Clinical significance

Mutations in the SUCLA2 gene are associated with mitochondrial DNA (mtDNA) depletion syndrome.[7][8] Symptoms include early onset low muscle tone, severe muscular atrophy, scoliosis, movement disorders such as dystonia and hyperkinesia, epilepsy, and growth retardation. Because succinic acid can not be made from succinyl coa, treatment is with oral succinic acid, which allows the krebs cycle, and electron transport chain to function correctly. Other treatments are managing symptoms and includes exercises to promote mobility, respiratory assistance, baclofen to treat dystonia and hyperkinesia, and antiepileptic drugs for seizures.[7][9]

There is a relatively high incidence of a specific SUCLA2 mutation in the Faroe Islands due to a founder effect. This particular mutation is often associated with early lethality.[10] Two additional founder mutations in have been discovered in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.[11] These patients show a higher variability in outcomes with a number of patients with SUCLA2 missense mutation surviving into adulthood. This variability suggests that SUCLA2 missense mutations may be associated with residual enzyme activity.[11]

Coenzyme Q10 and antioxidants have been used to treat mitochondrial DNA depletion syndrome but there is currently no evidence that these treatments result in clinical benefit.[9][12]

Mutations in the SUCLA2 gene leading to SUCLA2 deficiency result in Leigh's or a Leigh-like syndrome with onset of severe hypotonia, muscular atrophy, sensorineural hearing impairment, and often death in early childhood.[4][6]

See also

References

  1. ↑ 1.0 1.1 1.2 Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO (October 1998). "Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes". The Journal of Biological Chemistry. 273 (42): 27580–6. doi:10.1074/jbc.273.42.27580. PMID 9765291.
  2. ↑ 2.0 2.1 2.2 "Entrez Gene: SUCLA2 succinate-CoA ligase, ADP-forming, beta subunit".
  3. ↑ 3.0 3.1 Matilainen S, Isohanni P, Euro L, Lönnqvist T, Pihko H, Kivelä T, Knuutila S, Suomalainen A (March 2015). "Mitochondrial encephalomyopathy and retinoblastoma explained by compound heterozygosity of SUCLA2 point mutation and 13q14 deletion". European Journal of Human Genetics. 23 (3): 325–30. doi:10.1038/ejhg.2014.128. PMC 4326715. PMID 24986829.
  4. ↑ 4.0 4.1 4.2 4.3 Miller C, Wang L, Ostergaard E, Dan P, Saada A (May 2011). "The interplay between SUCLA2, SUCLG2, and mitochondrial DNA depletion". Biochimica et Biophysica Acta. 1812 (5): 625–9. doi:10.1016/j.bbadis.2011.01.013. PMID 21295139.
  5. ↑ 5.0 5.1 5.2 5.3 Dobolyi A, Bagó AG, Gál A, Molnár MJ, Palkovits M, Adam-Vizi V, Chinopoulos C (April 2015). "Localization of SUCLA2 and SUCLG2 subunits of succinyl CoA ligase within the cerebral cortex suggests the absence of matrix substrate-level phosphorylation in glial cells of the human brain". Journal of Bioenergetics and Biomembranes. 47 (1–2): 33–41. doi:10.1007/s10863-014-9586-4. PMID 25370487.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Dobolyi A, Ostergaard E, Bagó AG, Dóczi T, Palkovits M, Gál A, Molnár MJ, Adam-Vizi V, Chinopoulos C (January 2015). "Exclusive neuronal expression of SUCLA2 in the human brain". Brain Structure & Function. 220 (1): 135–51. doi:10.1007/s00429-013-0643-2. PMID 24085565.
  7. ↑ 7.0 7.1 Ostergaard E (May 2009). Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJ, Bird TD, Fong CT, Mefford HC, Smith RJ, Stephens K, eds. "SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form, with Mild Methylmalonic Acuduria". review. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle.
  8. ↑ El-Hattab AW, Scaglia F (April 2013). "Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options". review. Neurotherapeutics. 10 (2): 186–98. doi:10.1007/s13311-013-0177-6. PMC 3625391. PMID 23385875.
  9. ↑ 9.0 9.1 Parikh S, Saneto R, Falk MJ, Anselm I, Cohen BH, Haas R, Medicine Society TM (November 2009). "A modern approach to the treatment of mitochondrial disease". primary source. Current Treatment Options in Neurology. 11 (6): 414–30. doi:10.1007/s11940-009-0046-0. PMC 3561461. PMID 19891905.
  10. ↑ Ostergaard E, Hansen FJ, Sorensen N, Duno M, Vissing J, Larsen PL, Faeroe O, Thorgrimsson S, Wibrand F, Christensen E, Schwartz M (March 2007). "Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations". primary source. Brain. 130 (Pt 3): 853–61. doi:10.1093/brain/awl383. PMID 17287286.
  11. ↑ 11.0 11.1 Carrozzo R, Verrigni D, Rasmussen M, de Coo R, Amartino H, Bianchi M, Buhas D, Mesli S, Naess K, Born AP, Woldseth B, Prontera P, Batbayli M, Ravn K, Joensen F, Cordelli DM, Santorelli FM, Tulinius M, Darin N, Duno M, Jouvencel P, Burlina A, Stangoni G, Bertini E, Redonnet-Vernhet I, Wibrand F, Dionisi-Vici C, Uusimaa J, Vieira P, Osorio AN, McFarland R, Taylor RW, Holme E, Ostergaard E (March 2016). "Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients". primary source. Journal of Inherited Metabolic Disease. 39 (2): 243–52. doi:10.1007/s10545-015-9894-9. PMID 26475597.
  12. ↑ Pfeffer G, Majamaa K, Turnbull DM, Thorburn D, Chinnery PF (April 2012). "Treatment for mitochondrial disorders". review. The Cochrane Database of Systematic Reviews. 4 (4): CD004426. doi:10.1002/14651858.CD004426.pub3. PMID 22513923.

Further reading

External links

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