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{{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 uridylyltransferase''' (or '''GALT''') 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 = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2592| accessdate = }}</ref>
 
Galactose-1-phosphate uridylyltransferase (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:D-galactose Fischer.png|[[galactose]]
Image:D-glucose-chain-2D-Fischer.png|[[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 |author=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|url=}}</ref>  This means that the net reaction consists of two reactants and two products (see 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">http://www.mondofacto.com/facts/dictionary?double+displacement+mechanism</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 |author=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=11049–61 |date=September 1995 |pmid=7669762 |doi= 10.1021/bi00035a010|url=}}</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">http://web.virginia.edu/Heidi/chapter19/chp19frameset.htm</ref>]]
 
==Structural studies==
The three-dimensional structure at 1.8 angstrom resolution ([[x-ray crystallography]]) of GALT was discovered by Wedekind, Frey, and Rayment, and their structural analysis has found key [[amino acids]] essential for GALT function.<ref name="structure" />
 
The important amino acids that Wedekind et al. found in their structural analysis of GALT, such as Leu4, Phe75, Asn77, Asp78, Phe79, and Val108, are consistent with residues that have been implicated both in point mutation experiments as well as in clinical screening to play a role in human galactosemia.<ref name="structure" /><ref name="mutations">{{cite journal |author=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=Hum. Mutat. |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 |url=}}</ref>
 
==Clinical significance==
Deficiency of GALT causes [[classic galactosemia]].  [[Galactosemia]] is a childhood disease of hereditary nature.<ref name="Frido">{{cite journal |author=Fridovich-Keil JL |title=Galactosemia: the good, the bad, and the unknown |journal=J. Cell. Physiol. |volume=209 |issue=3 |pages=701–5 |date=December 2006 |pmid=17001680 |doi=10.1002/jcp.20820 |url=}}</ref>  The autosomal recessive trait affects 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 affliction, [[Duarte/Classica]] (D/G) arises from attenuation of GALT activity.<ref name="Elsas 1995">{{cite journal |author=Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP |title=A molecular approach to galactosemia |journal=Eur. J. Pediatr. |volume=154 |issue=7 Suppl 2 |pages=S21–7 |year=1995 |pmid=7671959 |doi= 10.1007/BF02143798|url=}}</ref>  Symptoms include ovarian failure, [[developmental coordination disorder]] (difficulty speaking correctly and consistently),<ref name="apraxia">http://www.nidcd.nih.gov/health/voice/apraxia.htm</ref> and neurologic deficits.<ref name="Elsas 1995" />  A single mutation in any of several amino acids can lead to attenuation or deficiency in GALT activity.<ref name="Dob">{{cite journal |author=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=J Mol Diagn |volume=5 |issue=1 |pages=42–7 |date=February 2003 |pmid=12552079 |pmc=1907369 |doi= 10.1016/S1525-1578(10)60450-3|url=}}</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 |author=Lai K, Elsas LJ, Wierenga KJ |title=Galactose toxicity in animals |journal=IUBMB Life |volume=61 |issue=11 |pages=1063–74 |date=November 2009 |pmid=19859980 |pmc=2788023 |doi=10.1002/iub.262 |url=}}</ref>  However, those afflicted with galactosemia can live relatively normal lives by avoiding milk products and anything else containing galactose (since it cannot be metabolized), although there is the potential for problems in neurological development, or other complications, even in those who avoid galactose.<ref name="med">http://www.umm.edu/ency/article/000366trt.htm</ref>
 
==Disease Database==
[http://www.arup.utah.edu/database/GALT/GALT_display.php Galactosemia (GALT) Mutation Database]
 
==References==
{{reflist}}
 
==Further reading==
{{refbegin | 2}}
{{PBB_Further_reading
| citations =
*{{cite journal  | author=Reichardt JK |title=Genetic basis of galactosemia |journal=Hum. Mutat. |volume=1 |issue= 3 |pages= 190–6 |year= 1993 |pmid= 1301925 |doi= 10.1002/humu.1380010303 }}
*{{cite journal  | author=Tyfield L, Reichardt J, Fridovich-Keil J, ''et al.'' |title=Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene |journal=Hum. Mutat. |volume=13 |issue= 6 |pages= 417–30 |year= 1999 |pmid= 10408771 |doi= 10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0 }}
*{{cite journal  | author=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 |year= 1992 |pmid= 1373122 |doi=10.1016/0888-7543(92)90453-Y  }}
*{{cite journal  | author=Leslie ND, Immerman EB, Flach JE, ''et al.'' |title=The human galactose-1-phosphate uridyltransferase gene |journal=Genomics |volume=14 |issue= 2 |pages= 474–80 |year= 1992 |pmid= 1427861 |doi=10.1016/S0888-7543(05)80244-7  }}
*{{cite journal  | author=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= 5430–3 |year= 1992 |pmid= 1610789 |doi=10.1021/bi00139a002  }}
*{{cite journal  | author=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=Am. J. Hum. Genet. |volume=49 |issue= 4 |pages= 860–7 |year= 1991 |pmid= 1897530 |doi=  | pmc=1683190  }}
*{{cite journal  | author=Reichardt JK, Woo SL |title=Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 7 |pages= 2633–7 |year= 1991 |pmid= 2011574 |doi=10.1073/pnas.88.7.2633  | pmc=51292  }}
*{{cite journal  | author=Flach JE, Reichardt JK, Elsas LJ |title=Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase |journal=Mol. Biol. Med. |volume=7 |issue= 4 |pages= 365–9 |year= 1990 |pmid= 2233247 |doi=  }}
*{{cite journal  | author=Reichardt JK, Berg P |title=Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyl transferase |journal=Mol. Biol. Med. |volume=5 |issue= 2 |pages= 107–22 |year= 1988 |pmid= 2840550 |doi=  }}
*{{cite journal  | author=Bergren WG, Donnell GN |title=A new variant of galactose-1-phosphate uridyltransferase in man: the Los Angeles variant |journal=Ann. Hum. Genet. |volume=37 |issue= 1 |pages= 1–8 |year= 1974 |pmid= 4759900 |doi=10.1111/j.1469-1809.1973.tb01808.x  }}
*{{cite journal  | author=Shih LY, Suslak L, Rosin I, ''et al.'' |title=Gene dosage studies supporting localization of the structural gene for galactose-1-phosphate uridyl transferase (GALT) to band p13 of chromosome 9 |journal=Am. J. Med. Genet. |volume=19 |issue= 3 |pages= 539–43 |year= 1985 |pmid= 6095663 |doi= 10.1002/ajmg.1320190316 }}
*{{cite journal  | author=Ashino J, Okano Y, Suyama I, ''et al.'' |title=Molecular characterization of galactosemia (type 1) mutations in Japanese |journal=Hum. Mutat. |volume=6 |issue= 1 |pages= 36–43 |year= 1995 |pmid= 7550229 |doi= 10.1002/humu.1380060108 }}
*{{cite journal  | author=Elsas LJ, Langley S, Paulk EM, ''et al.'' |title=A molecular approach to galactosemia |journal=Eur. J. Pediatr. |volume=154 |issue= 7 Suppl 2 |pages= S21–7 |year= 1995 |pmid= 7671959 |doi=10.1007/BF02143798  }}
*{{cite journal  | author=Elsas LJ, Langley S, Steele E, ''et al.'' |title=Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes |journal=Am. J. Hum. Genet. |volume=56 |issue= 3 |pages= 630–9 |year= 1995 |pmid= 7887416 |doi=  | pmc=1801164  }}
*{{cite journal  | author=Fridovich-Keil JL, Langley SD, Mazur LA, ''et al.'' |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=Am. J. Hum. Genet. |volume=56 |issue= 3 |pages= 640–6 |year= 1995 |pmid= 7887417 |doi=  | pmc=1801186  }}
*{{cite journal  | author=Davit-Spraul A, Pourci ML, Ng KH, ''et al.'' |title=Regulatory effects of galactose on galactose-1-phosphate uridyltransferase activity on human hepatoblastoma HepG2 cells |journal=FEBS Lett. |volume=354 |issue= 2 |pages= 232–6 |year= 1994 |pmid= 7957929 |doi=10.1016/0014-5793(94)01133-8  }}
*{{cite journal  | author=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=Hum. Genet. |volume=93 |issue= 2 |pages= 167–9 |year= 1994 |pmid= 8112740 |doi=10.1007/BF00210604  }}
*{{cite journal  | author=Elsas LJ, Dembure PP, Langley S, ''et al.'' |title=A common mutation associated with the Duarte galactosemia allele |journal=Am. J. Hum. Genet. |volume=54 |issue= 6 |pages= 1030–6 |year= 1994 |pmid= 8198125 |doi=  | pmc=1918187  }}
*{{cite journal  | author=Reichardt JK, Novelli G, Dallapiccola B |title=Molecular characterization of the H319Q galactosemia mutation |journal=Hum. Mol. Genet. |volume=2 |issue= 3 |pages= 325–6 |year= 1993 |pmid= 8499924 |doi=10.1093/hmg/2.3.325  }}
}}
{{refend}}
 
==External links==
* {{MeshName|Galactose-1-P-Uridyltransferase}}
* [http://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/galactosemia/GALT_welcome.php Galactosemia (GALT) Mutation Database]
* [http://bioinformatica.isa.cnr.it/GALT/ GALT Protein Database]
 
{{Phosphotransferases}}
{{Fructose and galactose metabolism}}
 
<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{PBB_Controls
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{{DEFAULTSORT:Galactose-1-phosphate uridylyltransferase}}
[[Category:EC 2.7.7]]
 
[[es:Galactosa-1-fosfato uridiltransferasa]]

Revision as of 08:25, 5 February 2014

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