Galactose-1-phosphate uridylyltransferase

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

NP_001289440
NP_057867

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
Symbol GalP_UDP_transf
Pfam PF01087
Pfam clan CL0265
PROSITE PDOC00108
SCOP 1hxp
SUPERFAMILY 1hxp
Galactose-1-phosphate uridyl transferase, C-terminal domain
structure of nucleotidyltransferase complexed with udp-galactose
Identifiers
Symbol GalP_UDP_tr_C
Pfam PF02744
Pfam clan CL0265
InterPro IPR005850
PROSITE PDOC00108
SCOP 1hxp
SUPERFAMILY 1hxp

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

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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000213930 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036073 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. 1 2 "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): 3889–3894. doi:10.1021/bi00716a011. PMID 4606575.
  7. ↑ http://www.mondofacto.com/facts/dictionary?double+displacement+mechanism
  8. 1 2 3 4 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. ↑ http://web.virginia.edu/Heidi/chapter19/chp19frameset.htm
  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". Hum. Mutat. 13 (4): 339. doi:10.1002/(SICI)1098-1004(1999)13:4<339::AID-HUMU18>3.0.CO;2-S. PMID 10220154.
  11. 1 2 Fridovich-Keil JL (December 2006). "Galactosemia: the good, the bad, and the unknown". J. Cell. Physiol. 209 (3): 701–5. doi:10.1002/jcp.20820. PMID 17001680.
  12. 1 2 3 4 Elsas LJ, Langley S, Paulk EM, Hjelm LN, Dembure PP (1995). "A molecular approach to galactosemia". Eur. J. Pediatr. 154 (7 Suppl 2): S21–7. doi:10.1007/BF02143798. PMID 7671959.
  13. ↑ "Archived copy". Archived from the original on 2006-02-28. Retrieved 2010-05-19.
  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". J Mol Diagn. 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

  • Reichardt JK (1993). "Genetic basis of galactosemia". Hum. Mutat. 1 (3): 190–6. doi:10.1002/humu.1380010303. PMID 1301925.
  • Tyfield L, Reichardt J, Fridovich-Keil J, et al. (1999). "Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene". Hum. Mutat. 13 (6): 417–30. doi:10.1002/(SICI)1098-1004(1999)13:6<417::AID-HUMU1>3.0.CO;2-0. PMID 10408771.
  • Reichardt JK, Belmont JW, Levy HL, Woo SL (1992). "Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia". Genomics. 12 (3): 596–600. doi:10.1016/0888-7543(92)90453-Y. PMID 1373122.
  • Leslie ND, Immerman EB, Flach JE, et al. (1992). "The human galactose-1-phosphate uridyltransferase gene". Genomics. 14 (2): 474–80. doi:10.1016/S0888-7543(05)80244-7. PMID 1427861.
  • Reichardt JK, Levy HL, Woo SL (1992). "Molecular characterization of two galactosemia mutations and one polymorphism: implications for structure-function analysis of human galactose-1-phosphate uridyltransferase". Biochemistry. 31 (24): 5430–3. doi:10.1021/bi00139a002. PMID 1610789.
  • Reichardt JK, Packman S, Woo SL (1991). "Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase". Am. J. Hum. Genet. 49 (4): 860–7. PMC 1683190. PMID 1897530.
  • Reichardt JK, Woo SL (1991). "Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase". Proc. Natl. Acad. Sci. U.S.A. 88 (7): 2633–7. doi:10.1073/pnas.88.7.2633. PMC 51292. PMID 2011574.
  • Flach JE, Reichardt JK, Elsas LJ (1990). "Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase". Mol. Biol. Med. 7 (4): 365–9. PMID 2233247.
  • Reichardt JK, Berg P (1988). "Cloning and characterization of a cDNA encoding human galactose-1-phosphate uridyl transferase". Mol. Biol. Med. 5 (2): 107–22. PMID 2840550.
  • Bergren WG, Donnell GN (1974). "A new variant of galactose-1-phosphate uridyltransferase in man: the Los Angeles variant". Ann. Hum. Genet. 37 (1): 1–8. doi:10.1111/j.1469-1809.1973.tb01808.x. PMID 4759900.
  • Shih LY, Suslak L, Rosin I, et al. (1985). "Gene dosage studies supporting localization of the structural gene for galactose-1-phosphate uridyl transferase (GALT) to band p13 of chromosome 9". Am. J. Med. Genet. 19 (3): 539–43. doi:10.1002/ajmg.1320190316. PMID 6095663.
  • Ashino J, Okano Y, Suyama I, et al. (1995). "Molecular characterization of galactosemia (type 1) mutations in Japanese". Hum. Mutat. 6 (1): 36–43. doi:10.1002/humu.1380060108. PMID 7550229.
  • Elsas LJ, Langley S, Paulk EM, et al. (1995). "A molecular approach to galactosemia". Eur. J. Pediatr. 154 (7 Suppl 2): S21–7. doi:10.1007/BF02143798. PMID 7671959.
  • Elsas LJ, Langley S, Steele E, et al. (1995). "Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes". Am. J. Hum. Genet. 56 (3): 630–9. PMC 1801164. PMID 7887416.
  • Fridovich-Keil JL, Langley SD, Mazur LA, et al. (1995). "Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family". Am. J. Hum. Genet. 56 (3): 640–6. PMC 1801186. PMID 7887417.
  • Davit-Spraul A, Pourci ML, Ng KH, et al. (1994). "Regulatory effects of galactose on galactose-1-phosphate uridyltransferase activity on human hepatoblastoma HepG2 cells". FEBS Lett. 354 (2): 232–6. doi:10.1016/0014-5793(94)01133-8. PMID 7957929.
  • Lin HC, Kirby LT, Ng WG, Reichardt JK (1994). "On the molecular nature of the Duarte variant of galactose-1-phosphate uridyl transferase (GALT)". Hum. Genet. 93 (2): 167–9. doi:10.1007/BF00210604. PMID 8112740.
  • Elsas LJ, Dembure PP, Langley S, et al. (1994). "A common mutation associated with the Duarte galactosemia allele". Am. J. Hum. Genet. 54 (6): 1030–6. PMC 1918187. PMID 8198125.
  • Reichardt JK, Novelli G, Dallapiccola B (1993). "Molecular characterization of the H319Q galactosemia mutation". Hum. Mol. Genet. 2 (3): 325–6. doi:10.1093/hmg/2.3.325. PMID 8499924.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.