Galactose-1-phosphate uridylyltransferase

Galactose-1-phosphate uridylyltransferase (or GALT) is an enzyme (EC 2.7.7.12) responsible for converting ingested galactose to glucose.[5]

GALT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGALT, entrez:2592, galactose-1-phosphate uridylyltransferase
External IDsOMIM: 606999 MGI: 95638 HomoloGene: 126 GeneCards: GALT
Gene location (Human)
Chr.Chromosome 9 (human)[1]
Band9p13.3Start34,638,133 bp[1]
End34,651,035 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

2592

14430

Ensembl

ENSG00000213930

ENSMUSG00000036073

UniProt

P07902

Q03249

RefSeq (mRNA)

NM_001258332
NM_000155

NM_016658
NM_001302511

RefSeq (protein)

NP_000146
NP_001245261

Location (UCSC)Chr 9: 34.64 – 34.65 MbChr 4: 41.76 – 41.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
Galactose-1-phosphate uridyl transferase, N-terminal domain
Identifiers
SymbolGalP_UDP_transf
PfamPF01087
Pfam clanCL0265
PROSITEPDOC00108
SCOP21hxp / SCOPe / SUPFAM
Galactose-1-phosphate uridyl transferase, C-terminal domain
structure of nucleotidyltransferase complexed with udp-galactose
Identifiers
SymbolGalP_UDP_tr_C
PfamPF02744
Pfam clanCL0265
InterProIPR005850
PROSITEPDOC00108
SCOP21hxp / SCOPe / SUPFAM

Galactose-1-phosphate uridylyltransferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely:

UDP-glucose + galactose 1-phosphate 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.[5]

Mechanism

GALT catalyzes the second reaction of the Leloir pathway of galactose metabolism through ping pong bi-bi kinetics with a double displacement mechanism.[6] 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.[7] 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.[8]

  1. UDP-glucose + E-His ⇌ Glucose-1-phosphate + E-His-UMP
  2. Galactose-1-phosphate + E-His-UMP ⇌ UDP-galactose + E-His[8]
Two-step action of galactose-1-phosphate uridylyltransferase. Image adapted from [9]

Structural studies

The three-dimensional structure at 180 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.[8] 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.[8][10]

Clinical significance

Deficiency of GALT causes classic galactosemia. Galactosemia is an autosomal recessive inherited disorder detectable in newborns and childhood.[11] 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, Duarte (D/D) and the Duarte/Classical variant (D/G) are caused by the attenuation of GALT activity.[12] Symptoms include ovarian failure, developmental coordination disorder (difficulty speaking correctly and consistently),[13] and neurologic deficits.[12] A single mutation in any of several base pairs can lead to deficiency in GALT activity.[14] 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.[12] These two mutations also add new restriction enzyme cut sites, which enable detection by and large-scale population screening with PCR (polymerase chain reaction).[12] 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.[11][15] 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.[16]

Disease database

Galactosemia (GALT) Mutation Database

References
  1. GRCh38: Ensembl release 89: ENSG00000213930 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000036073 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".
  6. Wong LJ, Frey PA (September 1974). "Galactose-1-phosphate uridylyltransferase: rate studies confirming a uridylyl-enzyme intermediate on the catalytic pathway". Biochemistry. 13 (19): 3889–94. doi:10.1021/bi00716a011. PMID 4606575.
  7. "Archived copy". Archived from the original on 2016-03-03. Retrieved 2010-05-19.CS1 maint: archived copy as title (link)
  8. Wedekind JE, Frey PA, Rayment I (September 1995). "Three-dimensional structure of galactose-1-phosphate uridylyltransferase from Escherichia coli at 1.8 A resolution". Biochemistry. 34 (35): 11049–61. doi:10.1021/bi00035a010. PMID 7669762.
  9. "Archived copy". Archived from the original on 2008-12-04. Retrieved 2010-05-19.CS1 maint: archived copy as title (link)
  10. Seyrantepe V, Ozguc M, Coskun T, Ozalp I, Reichardt JK (1999). "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". Human Mutation. 13 (4): 339. doi:10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU18>3.0.CO;2-S. PMID 10220154.
  11. Fridovich-Keil JL (December 2006). "Galactosemia: the good, the bad, and the unknown". Journal of Cellular Physiology. 209 (3): 701–5. doi:10.1002/jcp.20820. PMID 17001680. S2CID 32233614.
  12. Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995). "A molecular approach to galactosemia". European Journal of Pediatrics. 154 (7 Suppl 2): S21-7. doi:10.1007/BF02143798. PMID 7671959. S2CID 11937698.
  13. "Archived copy". Archived from the original on 2006-02-28. Retrieved 2010-05-19.CS1 maint: archived copy as title (link)
  14. Dobrowolski SF, Banas RA, Suzow JG, Berkley M, Naylor EW (February 2003). "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". The Journal of Molecular Diagnostics. 5 (1): 42–7. doi:10.1016/S1525-1578(10)60450-3. PMC 1907369. PMID 12552079.
  15. Lai K, Elsas LJ, Wierenga KJ (November 2009). "Galactose toxicity in animals". IUBMB Life. 61 (11): 1063–74. doi:10.1002/iub.262. PMC 2788023. PMID 19859980.
  16. http://www.umm.edu/ency/article/000366trt.htm

Further reading
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