Galactose-1-phosphate_uridyl_transferase

Galactose-1-phosphate uridylyltransferase

Galactose-1-phosphate uridylyltransferase

Mammalian protein found in Homo sapiens

Galactose-1-phosphate uridyltransferase (or GALT, G1PUT) is an enzyme (EC 2.7.7.12) responsible for converting ingested galactose to glucose.[5]

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Galactose-1-phosphate uridyltransferase (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]

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 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.[11]

Clinical significance

Deficiency of GALT causes classic galactosemia. Galactosemia is an autosomal recessive inherited disorder detectable in newborns and childhood.[12] 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.[13] Symptoms include ovarian failure, developmental coordination disorder (difficulty speaking correctly and consistently),[14] and neurologic deficits.[13] A single mutation in any of several base pairs can lead to deficiency in GALT activity.[15] 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.[13] These two mutations also add new restriction enzyme cut sites, which enable detection by and large-scale population screening with PCR (polymerase chain reaction).[13] 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.[12][16] 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.[17]

Disease database

Galactosemia (GALT) Mutation Database

References

  1. [1]
    GRCh38: Ensembl release 89: ENSG00000213930 – Ensembl, May 2017
  2. [2]
    GRCm38: Ensembl release 89: ENSMUSG00000036073 – Ensembl, May 2017
  3. [3]
    "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. [4]
    "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. [5]
    "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".
  6. [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. [7]
    "Double displacement mechanism - Definition". Archived from the original on 2016-03-03. Retrieved 2010-05-19.
  8. [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. [9]
    "Untitled Document". Archived from the original on 2008-12-04. Retrieved 2010-05-19.
  10. [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. [11]
    Ramakrishnan B, Qasba PK (2002-06-07). "Structure-based Design of β1,4-Galactosyltransferase I (β4Gal-T1) with Equally Efficient N-Acetylgalactosaminyltransferase Activity: POINT MUTATION BROADENS β4Gal-T1 DONOR SPECIFICITY*". Journal of Biological Chemistry. 277 (23): 20833–20839. doi:10.1074/jbc.M111183200. ISSN 0021-9258. PMID 11916963.
  12. [12]
    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.
  13. [13]
    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.
  14. [14]
    "Apraxia of Speech". Archived from the original on 2006-02-28. Retrieved 2010-05-19.
  15. [15]
    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.
  16. [16]
    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.
  17. [17]
    "Galactosemia - Treatment". Archived from the original on 2002-08-28.

Further reading

  1. [1]
    Beebe JA, Frey PA (1998-10-01). "Galactose Mutarotase: Purification, Characterization, and Investigations of Two Important Histidine Residues". Biochemistry. 37 (42): 14989–14997. doi:10.1021/bi9816047. ISSN 0006-2960.
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