View source for Galactose-1-phosphate uridylyltransferase

{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Short description|Mammalian protein found in Homo sapiens}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = GalP_UDP_transf
| Name = Galactose-1-phosphate uridyl transferase, N-terminal domain
| image =
| width = 
| caption = 
| Pfam = PF01087
| Pfam_clan = CL0265 
| InterPro = 
| SMART = 
| PROSITE = PDOC00108
| MEROPS = 
| SCOP = 1hxp
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = GalP_UDP_tr_C
| Name = Galactose-1-phosphate uridyl transferase, C-terminal domain
| image = PDB 1gup EBI.jpg
| width = 
| caption = structure of nucleotidyltransferase complexed with udp-galactose
| Pfam = PF02744
| Pfam_clan = CL0265 
| InterPro = IPR005850
| SMART = 
| PROSITE = PDOC00108
| MEROPS = 
| SCOP = 1hxp
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
'''Galactose-1-phosphate uridyltransferase''' (or '''GALT''', '''G1PUT''') is an [[enzyme]] ({{EC number|2.7.7.12}}) responsible for converting ingested [[galactose]] to [[glucose]].<ref name="entrez">{{cite web | title = Entrez Gene: GALT galactose-1-phosphate uridylyltransferase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2592}}</ref>

Galactose-1-phosphate uridyltransferase (GALT) catalyzes the second step of the [[Leloir pathway]] of [[galactose]] metabolism, namely:
:[[UDP-glucose]] + [[galactose 1-phosphate]] <math>\rightleftharpoons</math> [[glucose 1-phosphate]] + [[UDP-galactose]]
The expression of GALT is controlled by the actions of the [[FOXO3]] gene. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if [[lactose]] is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined.<ref name="entrez"/>

<gallery>
 Image:DGalactose Fischer.svg|[[galactose]]
 Image:D-glucose chain (Fischer).svg|[[glucose]]
</gallery>

==Mechanism==
GALT catalyzes the second reaction of the Leloir pathway of galactose metabolism through ping pong bi-bi [[chemical kinetics|kinetics]] with a [[double displacement]] mechanism.<ref name="test">{{cite journal | vauthors = Wong LJ, Frey PA | title = Galactose-1-phosphate uridylyltransferase: rate studies confirming a uridylyl-enzyme intermediate on the catalytic pathway | journal = Biochemistry | volume = 13 | issue = 19 | pages = 3889–3894 | date = September 1974 | pmid = 4606575 | doi = 10.1021/bi00716a011 }}</ref>  This means that the net reaction consists of two reactants and two products (see the reaction above) and it proceeds by the following mechanism: the enzyme reacts with one substrate to generate one product and a modified enzyme, which goes on to react with the second substrate to make the second product while regenerating the original enzyme.<ref name="bibi">{{Cite web |url=http://www.mondofacto.com/facts/dictionary?double+displacement+mechanism |title=Double displacement mechanism - Definition |access-date=2010-05-19 |archive-url=https://web.archive.org/web/20160303204044/http://www.mondofacto.com/facts/dictionary?double+displacement+mechanism |archive-date=2016-03-03 |url-status=dead }}</ref>  In the case of GALT, the His166 residue acts as a potent [[nucleophile]] to facilitate transfer of a nucleotide between UDP-hexoses and hexose-1-phosphates.<ref name="structure">{{cite journal | vauthors = Wedekind JE, Frey PA, Rayment I | title = Three-dimensional structure of galactose-1-phosphate uridylyltransferase from Escherichia coli at 1.8 A resolution | journal = Biochemistry | volume = 34 | issue = 35 | pages = 11049–11061 | date = September 1995 | pmid = 7669762 | doi = 10.1021/bi00035a010 }}</ref>

#UDP-glucose + E-His {{eqm}} Glucose-1-phosphate + E-His-UMP
#Galactose-1-phosphate + E-His-UMP {{eqm}} UDP-galactose + E-His<ref name="structure" />

[[Image:GALT.JPG|left|thumb|Two-step action of galactose-1-phosphate uridylyltransferase. Image adapted from <ref name="pic">{{Cite web |url=http://web.virginia.edu/Heidi/chapter19/chp19frameset.htm |title=Untitled Document |access-date=2010-05-19 |archive-url=https://web.archive.org/web/20081204112912/http://www.web.virginia.edu/Heidi/chapter19/chp19frameset.htm |archive-date=2008-12-04 |url-status=dead }}</ref>]]

==Structural studies==
The three-dimensional structure at 180 [[picometre|pm]] resolution ([[x-ray crystallography]]) of GALT was determined by Wedekind, Frey, and Rayment, and their structural analysis found key [[amino acids]] essential for GALT function.<ref name="structure" /> Among these are Leu4, Phe75, Asn77, Asp78, Phe79, and Val108, which are consistent with residues that have been implicated both in point mutation experiments as well as in clinical screening that play a role in human galactosemia.<ref name="structure" /><ref name="mutations">{{cite journal | vauthors = Seyrantepe V, Ozguc M, Coskun T, Ozalp I, Reichardt JK | title = Identification of mutations in the galactose-1-phosphate uridyltransferase (GALT) gene in 16 Turkish patients with galactosemia, including a novel mutation of F294Y. Mutation in brief no. 235. Online | journal = Human Mutation | volume = 13 | issue = 4 | pages = 339 | year = 1999 | pmid = 10220154 | doi = 10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU18>3.0.CO;2-S | doi-access = free }}</ref>

GALT also has minimal (~0.1%) GalNAc transferase activity. X-ray crystallography revealed that the side chain of Tyr289 forms a hydrogen bond with the ''N''-acetyl group of [[Uridine diphosphate N-acetylgalactosamine|UDP-GalNAc]]. Point mutation of residue Tyr289 to Leu, Ile, or Asn eliminates this interaction, enhancing GalNAc transferase activity, with the Y289L mutation showing comparable GalNAc transferase activity as the wild-type enzyme's Gal transferase activity.<ref>{{cite journal | vauthors = Ramakrishnan B, Qasba PK | title = Structure-based design of beta 1,4-galactosyltransferase I (beta 4Gal-T1) with equally efficient N-acetylgalactosaminyltransferase activity: point mutation broadens beta 4Gal-T1 donor specificity | journal = The Journal of Biological Chemistry | volume = 277 | issue = 23 | pages = 20833–20839 | date = June 2002 | pmid = 11916963 | doi = 10.1074/jbc.M111183200 | doi-access = free }}</ref>

==Clinical significance==
Deficiency of GALT causes [[classic galactosemia]].  [[Galactosemia]] is an autosomal recessive inherited disorder detectable in newborns and childhood.<ref name="Frido">{{cite journal | vauthors = Fridovich-Keil JL | title = Galactosemia: the good, the bad, and the unknown | journal = Journal of Cellular Physiology | volume = 209 | issue = 3 | pages = 701–705 | date = December 2006 | pmid = 17001680 | doi = 10.1002/jcp.20820 | s2cid = 32233614 }}</ref>  It occurs at approximately 1 in every 40,000-60,000 live-born infants.  [[Classical galactosemia]] (G/G) is caused by a deficiency in GALT activity, whereas the more common clinical manifestations, [[Galactose-1-phosphate uridylyltransferase deficiency#Genetics|Duarte (D/D) and the Duarte/Classical variant (D/G)]] are caused by the attenuation of GALT activity.<ref name="Elsas 1995">{{cite journal | vauthors = Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP | title = A molecular approach to galactosemia | journal = European Journal of Pediatrics | volume = 154 | issue = 7 Suppl 2 | pages = S21–S27 | year = 1995 | pmid = 7671959 | doi = 10.1007/BF02143798 | s2cid = 11937698 }}</ref>  Symptoms include ovarian failure, [[developmental coordination disorder]] (difficulty speaking correctly and consistently),<ref name="apraxia">{{cite web |url=http://www.nidcd.nih.gov/health/voice/apraxia.htm |title=Apraxia of Speech |access-date=2010-05-19 |url-status=dead |archive-url=https://web.archive.org/web/20060228083020/http://www.nidcd.nih.gov/health/voice/apraxia.htm |archive-date=2006-02-28 }}</ref> and neurologic deficits.<ref name="Elsas 1995" /> A single mutation in any of several base pairs can lead to deficiency in GALT activity.<ref name="Dob">{{cite journal | vauthors = Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW | title = Analysis of common mutations in the galactose-1-phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia | journal = The Journal of Molecular Diagnostics | volume = 5 | issue = 1 | pages = 42–47 | date = February 2003 | pmid = 12552079 | pmc = 1907369 | doi = 10.1016/S1525-1578(10)60450-3 }}</ref> For example, a single mutation from A to G in exon 6 of the GALT gene changes Glu188 to an [[arginine]] and a mutation from A to G in exon 10 converts Asn314 to an [[aspartic acid]].<ref name="Elsas 1995" />  These two mutations also add new [[restriction enzyme]] cut sites, which enable detection by and large-scale population screening with PCR ([[polymerase chain reaction]]).<ref name="Elsas 1995" /> Screening has mostly eliminated neonatal death by G/G galactosemia, but the disease, due to GALT’s role in the biochemical [[metabolism]] of ingested [[galactose]] (which is toxic when accumulated) to the energetically useful [[glucose]], can certainly be fatal.<ref name="Frido" /><ref name="lethal">{{cite journal | vauthors = Lai K, Elsas LJ, Wierenga KJ | title = Galactose toxicity in animals | journal = IUBMB Life | volume = 61 | issue = 11 | pages = 1063–1074 | date = November 2009 | pmid = 19859980 | pmc = 2788023 | doi = 10.1002/iub.262 }}</ref> However, those afflicted with galactosemia can live relatively normal lives by avoiding milk products and anything else containing galactose (because it cannot be metabolized), but there is still the potential for problems in neurological development or other complications, even in those who avoid galactose.<ref name="med">{{cite web |url=http://www.umm.edu/ency/article/000366trt.htm |url-status=dead |archive-url=https://web.archive.org/web/20020828095734/http://www.umm.edu/ency/article/000366trt.htm |archive-date=2002-08-28 |title=Galactosemia - Treatment}}</ref>

==Disease database==
[http://www.arup.utah.edu/database/GALT/GALT_display.php Galactosemia (GALT) Mutation Database]{{clear}}

== References ==
{{reflist|30em}}

== Further reading ==
{{refbegin|30em}}
* {{cite journal | vauthors = Reichardt JK | title = Genetic basis of galactosemia | journal = Human Mutation | volume = 1 | issue = 3 | pages = 190–196 | year = 1993 | pmid = 1301925 | doi = 10.1002/humu.1380010303 | s2cid = 504197 | doi-access = free }}
* {{cite journal | vauthors = Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD | display-authors = 6 | title = Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene | journal = Human Mutation | volume = 13 | issue = 6 | pages = 417–430 | year = 1999 | pmid = 10408771 | doi = 10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0 | s2cid = 34860932 }}
* {{cite journal | vauthors = Reichardt JK, Belmont JW, Levy HL, Woo SL | title = Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia | journal = Genomics | volume = 12 | issue = 3 | pages = 596–600 | date = March 1992 | pmid = 1373122 | doi = 10.1016/0888-7543(92)90453-Y }}
* {{cite journal | vauthors = Leslie ND, Immerman EB, Flach JE, Florez M, Fridovich-Keil JL, Elsas LJ | title = The human galactose-1-phosphate uridyltransferase gene | journal = Genomics | volume = 14 | issue = 2 | pages = 474–480 | date = October 1992 | pmid = 1427861 | doi = 10.1016/S0888-7543(05)80244-7 }}
* {{cite journal | vauthors = Reichardt JK, Levy HL, Woo SL | title = Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase | journal = Biochemistry | volume = 31 | issue = 24 | pages = 5430–5433 | date = June 1992 | pmid = 1610789 | doi = 10.1021/bi00139a002 }}
* {{cite journal | vauthors = Reichardt JK, Packman S, Woo SL | title = Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase | journal = American Journal of Human Genetics | volume = 49 | issue = 4 | pages = 860–867 | date = October 1991 | pmid = 1897530 | pmc = 1683190 }}
* {{cite journal | vauthors = Reichardt JK, Woo SL | title = Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 7 | pages = 2633–2637 | date = April 1991 | pmid = 2011574 | pmc = 51292 | doi = 10.1073/pnas.88.7.2633 | doi-access = free | bibcode = 1991PNAS...88.2633R }}
* {{cite journal | vauthors = Flach JE, Reichardt JK, Elsas LJ | title = Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase | journal = Molecular Biology & Medicine | volume = 7 | issue = 4 | pages = 365–369 | date = August 1990 | pmid = 2233247 }}
* {{cite journal | vauthors = Reichardt JK, Berg P | title = Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyl transferase | journal = Molecular Biology & Medicine | volume = 5 | issue = 2 | pages = 107–122 | date = April 1988 | pmid = 2840550 }}
* {{cite journal | vauthors = Bergren WG, Donnell GN | title = A new variant of galactose-1-phosphate uridyltransferase in man: the Los Angeles variant | journal = Annals of Human Genetics | volume = 37 | issue = 1 | pages = 1–8 | date = July 1973 | pmid = 4759900 | doi = 10.1111/j.1469-1809.1973.tb01808.x | s2cid = 22699183 }}
* {{cite journal | vauthors = Shih LY, Suslak L, Rosin I, Searle BM, Desposito F | title = Gene dosage studies supporting localization of the structural gene for galactose-1-phosphate uridyl transferase (GALT) to band p13 of chromosome 9 | journal = American Journal of Medical Genetics | volume = 19 | issue = 3 | pages = 539–543 | date = November 1984 | pmid = 6095663 | doi = 10.1002/ajmg.1320190316 }}
* {{cite journal | vauthors = Ashino J, Okano Y, Suyama I, Yamazaki T, Yoshino M, Furuyama J, Lin HC, Reichardt JK, Isshiki G | display-authors = 6 | title = Molecular characterization of galactosemia (type 1) mutations in Japanese | journal = Human Mutation | volume = 6 | issue = 1 | pages = 36–43 | year = 1995 | pmid = 7550229 | doi = 10.1002/humu.1380060108 | s2cid = 23500152 | doi-access = free }}
* {{cite journal | vauthors = Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP | title = A molecular approach to galactosemia | journal = European Journal of Pediatrics | volume = 154 | issue = 7 Suppl 2 | pages = S21–S27 | year = 1995 | pmid = 7671959 | doi = 10.1007/BF02143798 | s2cid = 11937698 }}
* {{cite journal | vauthors = Elsas LJ, Langley S, Steele E, Evinger J, Fridovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP | display-authors = 6 | title = Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes | journal = American Journal of Human Genetics | volume = 56 | issue = 3 | pages = 630–639 | date = March 1995 | pmid = 7887416 | pmc = 1801164 }}
* {{cite journal | vauthors = Fridovich-Keil JL, Langley SD, Mazur LA, Lennon JC, Dembure PP, Elsas JL | title = Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family | journal = American Journal of Human Genetics | volume = 56 | issue = 3 | pages = 640–646 | date = March 1995 | pmid = 7887417 | pmc = 1801186 }}
* {{cite journal | vauthors = Davit-Spraul A, Pourci ML, Ng KH, Soni T, Lemonnier A | title = Regulatory effects of galactose on galactose-1-phosphate uridyltransferase activity on human hepatoblastoma HepG2 cells | journal = FEBS Letters | volume = 354 | issue = 2 | pages = 232–236 | date = November 1994 | pmid = 7957929 | doi = 10.1016/0014-5793(94)01133-8 | s2cid = 45242645 | doi-access = free | bibcode = 1994FEBSL.354..232D }}
* {{cite journal | vauthors = Lin HC, Kirby LT, Ng WG, Reichardt JK | title = On the molecular nature of the Duarte variant of galactose-1-phosphate uridyl transferase (GALT) | journal = Human Genetics | volume = 93 | issue = 2 | pages = 167–169 | date = February 1994 | pmid = 8112740 | doi = 10.1007/BF00210604 | s2cid = 42558872 }}
* {{cite journal | vauthors = Elsas LJ, Dembure PP, Langley S, Paulk EM, Hjelm LN, Fridovich-Keil J | title = A common mutation associated with the Duarte galactosemia allele | journal = American Journal of Human Genetics | volume = 54 | issue = 6 | pages = 1030–1036 | date = June 1994 | pmid = 8198125 | pmc = 1918187 }}
* {{cite journal | vauthors = Reichardt JK, Novelli G, Dallapiccola B | title = Molecular characterization of the H319Q galactosemia mutation | journal = Human Molecular Genetics | volume = 2 | issue = 3 | pages = 325–326 | date = March 1993 | pmid = 8499924 | doi = 10.1093/hmg/2.3.325 }}
{{refend}}

== External links ==
* {{MeshName|Galactose-1-P-Uridyltransferase}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=galactosemia  GeneReviews/NIH/NCBI/UW entry on Galactosemia]  
* [http://www.arup.utah.edu/database/GALT/GALT_welcome.php Galactosemia (GALT) Mutation Database]
* [http://bioinformatica.isa.cnr.it/GALT/ GALT Protein Database]
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P07902 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Galactose-1-phosphate uridylyltransferase

{{Fructose and galactose metabolism}}
{{Kinases}}
{{Enzymes}}
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{{DEFAULTSORT:Galactose-1-phosphate uridylyltransferase}}
[[Category:EC 2.7.7]]