Galactose-1-phosphate uridylyltransferase

Source: Wikipedia, the free encyclopedia.
GALT
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_001258332
NM_000155
NM_147131
NM_147132

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
SCOP2
1hxp / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Galactose-1-phosphate uridyl transferase, C-terminal domain
SCOP2
1hxp / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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

Galactose-1-phosphate uridyltransferase (GALT) catalyzes the second step of the

Leloir pathway of galactose
metabolism, namely:

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

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

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

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. ^ a b c GRCh38: Ensembl release 89: ENSG00000213930 - Ensembl, May 2017
  2. ^ a b c 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. ^ a b "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".
  6. PMID 4606575
    .
  7. ^ "Double displacement mechanism - Definition". Archived from the original on 2016-03-03. Retrieved 2010-05-19.
  8. ^
    PMID 7669762
    .
  9. ^ "Untitled Document". Archived from the original on 2008-12-04. Retrieved 2010-05-19.
  10. PMID 10220154
    .
  11. .
  12. ^ .
  13. ^ .
  14. ^ "Apraxia of Speech". Archived from the original on 2006-02-28. Retrieved 2010-05-19.
  15. PMID 12552079
    .
  16. .
  17. ^ "Galactosemia - Treatment". Archived from the original on 2002-08-28.

Further reading

External links