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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''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 Research | volume = 6 | issue = 10 | pages = 922–34 | date = October 1996 | 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 = The Journal of Biological Chemistry | volume = 276 | issue = 36 | pages = 33512–7 | date = September 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| access-date = }}</ref> Mutations in the ''TMLHE'' gene resulting in [[carnitine biosynthesis]] disruption have been associated with autism symptoms.<ref name=":0">{{cite journal | vauthors = Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP | title = Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation | journal = American Journal of Medical Genetics. Part A | volume = 167A | issue = 9 | pages = 2162–7 | date = September 2015 | pmid = 25943046 | doi = 10.1002/ajmg.a.37144 }}</ref>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{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>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
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 dependent 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>
{{PBB_Summary
| section_title =  
| summary_text =  
}}


==References==
== Function ==
{{reflist|2}}
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):
==Further reading==
 
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 may increase the risks of developing [[neurodevelopmental disorder]]s, [[autism]]-related behaviors, and [[Autism spectrum disorders]].<ref>http://www.omim.org/entry/300872</ref><ref name=":0" />
 
== Interactions ==
THLHE has been shown to have 14 binary [[Protein–protein interaction|protein-protein interactions]] including 12 co-complex interactions. THLHE appears to interact with SUGCT.<ref>{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=TMLHE | title = 14 binary interactions found for search term TMLHE | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}</ref>
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
| citations =
* {{cite journal | vauthors = Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S | title = Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing | journal = EMBO Reports | volume = 1 | issue = 3 | pages = 287–92 | date = September 2000 | pmid = 11256614 | pmc = 1083732 | doi = 10.1093/embo-reports/kvd058 }}
*{{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 = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
*{{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 = 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 = Journal of Cellular Physiology | volume = 204 | issue = 3 | pages = 839–47 | date = September 2005 | pmid = 15754339 | doi = 10.1002/jcp.20332 }}
*{{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 = 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 | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415-8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
*{{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 = 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 | date = June 2007 | pmid = 17408883 | doi = 10.1016/j.gene.2007.02.012 }}
*{{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  | 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  | 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  | 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 | 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 | 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  | 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}}


{{protein-stub}}
{{protein-stub}}
{{WikiDoc Sources}}

Latest revision as of 10:40, 12 January 2019

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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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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Trimethyllysine dioxygenase, mitochondrial is an enzyme that in humans is encoded by the TMLHE gene in chromosome X.[1][2][3] Mutations in the TMLHE gene resulting in carnitine biosynthesis disruption have been associated with autism symptoms.[4]

Structure

The TMHLE gene is located at the extreme end of the Xq28 region with high genomic instability,[5] and encodes a protein trimethyllysine dioxygenase, a, Fe2+ and 2-oxoglytarate dependent non-heme-ferrous iron hydrolase localized to the mitochondrial matrix.[6]

Function

The trimethyllysine dioxygenase enzyme catalyzes the first step in the carnitine biosynthesis pathway,[6] 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),[7][8] an inborn error of metabolism in carnitine biosynthesis, which may increase the risks of developing neurodevelopmental disorders, autism-related behaviors, and Autism spectrum disorders.[9][4]

Interactions

THLHE has been shown to have 14 binary protein-protein interactions including 12 co-complex interactions. THLHE appears to interact with SUGCT.[10]

References

  1. ↑ Rogner UC, Heiss NS, Kioschis P, Wiemann S, Korn B, Poustka A (October 1996). "Transcriptional analysis of the candidate region for incontinentia pigmenti (IP2) in Xq28". Genome Research. 6 (10): 922–34. doi:10.1101/gr.6.10.922. PMID 8908511.
  2. ↑ Vaz FM, Ofman R, Westinga K, Back JW, Wanders RJ (September 2001). "Molecular and Biochemical Characterization of Rat epsilon -N-Trimethyllysine Hydroxylase, the First Enzyme of Carnitine Biosynthesis". The Journal of Biological Chemistry. 276 (36): 33512–7. doi:10.1074/jbc.M105929200. PMID 11431483.
  3. ↑ "Entrez Gene: TMLHE trimethyllysine hydroxylase, epsilon".
  4. ↑ 4.0 4.1 Ziats MN, Comeaux MS, Yang Y, Scaglia F, Elsea SH, Sun Q, Beaudet AL, Schaaf CP (September 2015). "Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation". American Journal of Medical Genetics. Part A. 167A (9): 2162–7. doi:10.1002/ajmg.a.37144. PMID 25943046.
  5. ↑ 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ http://www.omim.org/entry/300872
  10. ↑ "14 binary interactions found for search term TMLHE". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading


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