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{{Infobox_gene}}
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'''Trimethyllysine dioxygenase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''TMLHE'' [[gene]] in [[chromosome X]].<ref name="pmid8908511">{{cite journal | vauthors = Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A | title = Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28 | journal = Genome Res | volume = 6 | issue = 10 | pages = 922–34 |date=Feb 1997 | pmid = 8908511 | pmc =  | doi =10.1101/gr.6.10.922 }}</ref><ref name="pmid11431483">{{cite journal | vauthors = Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ | title = Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis | journal = J Biol Chem | volume = 276 | issue = 36 | pages = 33512–7 |date=Sep 2001 | pmid = 11431483 | pmc =  | doi = 10.1074/jbc.M105929200 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55217| accessdate = }}</ref>
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{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Trimethyllysine hydroxylase, epsilon
| HGNCid = 18308
| Symbol = TMLHE
| AltSymbols =; BBOX2; FLJ10727; TMLH; XAP130
| OMIM =
| ECnumber =
  | Homologene = 21853
| MGIid =   
| Function = {{GNF_GO|id=GO:0005506 |text = iron ion binding}} {{GNF_GO|id=GO:0016491 |text = oxidoreductase activity}} {{GNF_GO|id=GO:0016702 |text = oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen}} {{GNF_GO|id=GO:0031418 |text = L-ascorbic acid binding}} {{GNF_GO|id=GO:0050353 |text = trimethyllysine dioxygenase activity}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
  | Process = {{GNF_GO|id=GO:0006118 |text = electron transport}} {{GNF_GO|id=GO:0045329 |text = carnitine biosynthetic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 55217
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_060666
    | Hs_RefseqmRNA = NM_018196
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = 
    | Mm_RefseqProtein = 
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Trimethyllysine hydroxylase, epsilon''', also known as '''TMLHE''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=55217| accessdate = }}</ref>


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==Structure==
The ''TMHLE'' gene is located at the extreme end of the Xq28 region with high genomic instability,<ref>{{vcite2 journal |vauthors=Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, Ursini MV |title=Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants |journal=Gene |volume=395 |issue=1-2 |pages=86–97 |year=2007 |pmid=17408883 |doi=10.1016/j.gene.2007.02.012 |url=}}</ref> and encodes a protein trimethyllysine dioxygenase, a , Fe2+ and 2-oxoglytarate dependen non-heme-ferrous iron hydrolase localized to the [[mitochondrial matrix]].<ref name="ReferenceA">{{vcite2 journal |vauthors=Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, D'Urso M, Vaz FM, Ursini MV |title=Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting |journal=J. Cell. Physiol. |volume=204 |issue=3 |pages=839–47 |year=2005 |pmid=15754339 |doi=10.1002/jcp.20332 |url=}}</ref>
==Function==
The trimethyllysine dioxygenase enzyme catalyzes the first step in the [[carnitine]] biosynthesis pathway,<ref name="ReferenceA"/> which is part of amine biosynthesis. [[Carnitine]] is a molecule that play an essential role in the transport of activated [[fatty acids]] across the [[inner mitochondrial membrane]] where they are metabolized. The encoded protein converts [[trimethyllysine]] into [[hydroxytrimethyllysine]] with the reaction (EC 1.14.11.8):
N<sub>6</sub>,N<sub>6</sub>,N(6)-trimethyl-L-lysine + 2-oxoglutarate + O<sub>2</sub> = 3-hydroxy-N<sub>6</sub>,N<sub>6</sub>,N(6)-trimethyl-L-lysine + succinate + CO<sub>2</sub>.
and requires [[iron]] and L-[[ascorbate]] as [[co-factors]].
== Clinical Significance ==
[[Mutations]] in the THLHE gene causes [[Epsilon-trimethyllysine hydroxylase deficiency]] (TMLHED),<ref>{{vcite2 journal |vauthors=Celestino-Soper PB, Shaw CA, Sanders SJ, Li J, Murtha MT, Ercan-Sencicek AG, Davis L, Thomson S, Gambin T, Chinault AC, Ou Z, German JR, Milosavljevic A, Sutcliffe JS, Cook EH, Stankiewicz P, State MW, Beaudet AL |title=Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE |journal=Hum. Mol. Genet. |volume=20 |issue=22 |pages=4360–70 |year=2011 |pmid=21865298 |pmc=3196886 |doi=10.1093/hmg/ddr363 |url=}}</ref><ref>{{vcite2 journal |vauthors=Nava C, Lamari F, Héron D, Mignot C, Rastetter A, Keren B, Cohen D, Faudet A, Bouteiller D, Gilleron M, Jacquette A, Whalen S, Afenjar A, Périsse D, Laurent C, Dupuits C, Gautier C, Gérard M, Huguet G, Caillet S, Leheup B, Leboyer M, Gillberg C, Delorme R, Bourgeron T, Brice A, Depienne C |title=Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE |journal=Transl Psychiatry |volume=2 |issue= |pages=e179 |year=2012 |pmid=23092983 |pmc=3565810 |doi=10.1038/tp.2012.102 |url=}}</ref> an [[inborn error of metabolism]] in carnitine biosynthesis, which is increased with risks for developing [[autism]]-related behaviours and [[Autism spectrum disorders]] <ref>http://www.omim.org/entry/300872</ref>


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal  | author=Rogner UC, Heiss NS, Kioschis P, ''et al.'' |title=Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28. |journal=Genome Res. |volume=6 |issue= 10 |pages= 922-34 |year= 1997 |pmid= 8908511 |doi=  }}
*{{cite journal  | vauthors=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788–95 |year= 2001 |pmid= 11076863 |doi=10.1101/gr.143000  | pmc=310948 }}
*{{cite journal  | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi=  }}
*{{cite journal   |vauthors=Simpson JC, Wellenreuther R, Poustka A, etal |title=Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. |journal=EMBO Rep. |volume=1 |issue= 3 |pages= 287–92 |year= 2001 |pmid= 11256614 |doi= 10.1093/embo-reports/kvd058  | pmc=1083732 }}
*{{cite journal | author=Simpson JC, Wellenreuther R, Poustka A, ''et al.'' |title=Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. |journal=EMBO Rep. |volume=1 |issue= 3 |pages= 287-92 |year= 2001 |pmid= 11256614 |doi= 10.1093/embo-reports/kvd058 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |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 | pmc=139241 }}
*{{cite journal | author=Vaz FM, Ofman R, Westinga K, ''et al.'' |title=Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis. |journal=J. Biol. Chem. |volume=276 |issue= 36 |pages= 33512-7 |year= 2001 |pmid= 11431483 |doi= 10.1074/jbc.M105929200 }}
*{{cite journal   |vauthors=Ota T, Suzuki Y, Nishikawa T, etal |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 }}
*{{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 }}
*{{cite journal   |vauthors=Gerhard DS, Wagner L, Feingold EA, etal |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 | pmc=528928 }}
*{{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 }}
*{{cite journal   |vauthors=Wiemann S, Arlt D, Huber W, etal |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136–44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 | pmc=528930 }}
*{{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 }}
*{{cite journal   |vauthors=Monfregola J, Cevenini A, Terracciano A, etal |title=Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting. |journal=J. Cell. Physiol. |volume=204 |issue= 3 |pages= 839–47 |year= 2005 |pmid= 15754339 |doi= 10.1002/jcp.20332 }}
*{{cite journal | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
*{{cite journal   |vauthors=Ross MT, Grafham DV, Coffey AJ, etal |title=The DNA sequence of the human X chromosome. |journal=Nature |volume=434 |issue= 7031 |pages= 325–37 |year= 2005 |pmid= 15772651 |doi= 10.1038/nature03440 | pmc=2665286 }}
*{{cite journal | author=Monfregola J, Cevenini A, Terracciano A, ''et al.'' |title=Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting. |journal=J. Cell. Physiol. |volume=204 |issue= 3 |pages= 839-47 |year= 2005 |pmid= 15754339 |doi= 10.1002/jcp.20332 }}
*{{cite journal   |vauthors=Mehrle A, Rosenfelder H, Schupp I, etal |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415–8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 | pmc=1347501 }}
*{{cite journal | author=Ross MT, Grafham DV, Coffey AJ, ''et al.'' |title=The DNA sequence of the human X chromosome. |journal=Nature |volume=434 |issue= 7031 |pages= 325-37 |year= 2005 |pmid= 15772651 |doi= 10.1038/nature03440 }}
*{{cite journal   |vauthors=Monfregola J, Napolitano G, Conte I, etal |title=Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants. |journal=Gene |volume=395 |issue= 1–2 |pages= 86–97 |year= 2007 |pmid= 17408883 |doi= 10.1016/j.gene.2007.02.012 }}
*{{cite journal | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
*{{cite journal | author=Monfregola J, Napolitano G, Conte I, ''et al.'' |title=Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants. |journal=Gene |volume=395 |issue= 1-2 |pages= 86-97 |year= 2007 |pmid= 17408883 |doi= 10.1016/j.gene.2007.02.012 }}
}}
}}
{{refend}}
{{refend}}
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Revision as of 12:02, 15 September 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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View/Edit Human

Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X.[1][2][3]


Structure

The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability,[4] and encodes a protein trimethyllysine dioxygenase, a , Fe2+ and 2-oxoglytarate dependen non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.[5]

Function

The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway,[5] which is part of amine biosynthesis. Carnitine is a molecule that play an essential role in the transport of activated fatty acids across the inner mitochondrial membrane where they are metabolized. The encoded protein converts trimethyllysine into hydroxytrimethyllysine with the reaction (EC 1.14.11.8):

N6,N6,N(6)-trimethyl-L-lysine + 2-oxoglutarate + O2 = 3-hydroxy-N6,N6,N(6)-trimethyl-L-lysine + succinate + CO2.

and requires iron and L-ascorbate as co-factors.

Clinical Significance

Mutations in the THLHE gene causes Epsilon-trimethyllysine hydroxylase deficiency (TMLHED),[6][7] an inborn error of metabolism in carnitine biosynthesis, which is increased with risks for developing autism-related behaviours and Autism spectrum disorders [8]

References

  1. ↑ Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A (Feb 1997). "Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28". Genome Res. 6 (10): 922–34. doi:10.1101/gr.6.10.922. PMID 8908511.
  2. ↑ Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ (Sep 2001). "Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis". J Biol Chem. 276 (36): 33512–7. doi:10.1074/jbc.M105929200. PMID 11431483.
  3. ↑ "Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon".
  4. ↑ Monfregola J, Napolitano G, Conte I, Cevenini A, Migliaccio C, D'Urso M, et al. (2007). "Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants". Gene. 395 (1–2): 86–97. doi:10.1016/j.gene.2007.02.012. PMID 17408883.
  5. ↑ 5.0 5.1 Monfregola J, Cevenini A, Terracciano A, van Vlies N, Arbucci S, Wanders RJ, et al. (2005). "Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting". J. Cell. Physiol. 204 (3): 839–47. doi:10.1002/jcp.20332. PMID 15754339.
  6. ↑ Celestino-Soper PB, Shaw CA, Sanders SJ, Li J, Murtha MT, Ercan-Sencicek AG, et al. (2011). "Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE". Hum. Mol. Genet. 20 (22): 4360–70. doi:10.1093/hmg/ddr363. PMC 3196886. PMID 21865298.
  7. ↑ Nava C, Lamari F, Héron D, Mignot C, Rastetter A, Keren B, et al. (2012). "Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE". Transl Psychiatry. 2: e179. doi:10.1038/tp.2012.102. PMC 3565810. PMID 23092983.
  8. ↑ http://www.omim.org/entry/300872

Further reading



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