Galactose—1-phosphate uridylyltransferase

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Galactose-1-phosphate uridylyltransferase
Galactose-1-phosphate uridylyltransferase 1GUP.png
Cartoon diagram of an E. coli GALT dimer in complex with UDP-galactose. From PDB 1GUP.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol GALT
External IDs OMIM606999 MGI95638 HomoloGene126 GeneCards: GALT Gene
EC number 2.7.7.12
Orthologs
Species Human Mouse
Entrez 2592 14430
Ensembl ENSG00000213930 ENSMUSG00000036073
UniProt P07902 Q03249
RefSeq (mRNA) NM_000155 NM_016658
RefSeq (protein) NP_000146 NP_057867
Location (UCSC) Chr 9:
34.64 – 34.65 Mb
Chr 4:
41.76 – 41.76 Mb
PubMed search [1] [2]
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
PDB 1gup EBI.jpg
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.[1]

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

UDP-glucose + galactose 1-phosphate \rightleftharpoons 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.[1]

Mechanism[edit]

GALT catalyzes the second reaction of the Leloir pathway of galactose metabolism through ping pong bi-bi kinetics with a double displacement mechanism.[2] 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.[3] 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.[4]

  1. UDP-glucose + E-His is in equilibrium with Glucose-1-phosphate + E-His-UMP
  2. Galactose-1-phosphate + E-His-UMP is in equilibrium with UDP-galactose + E-His[4]
Two-step action of galactose-1-phosphate uridylyltransferase. Image adapted from [5]

Structural studies[edit]

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.[4]

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.[4][6]

Clinical significance[edit]

Deficiency of GALT causes classic galactosemia. Galactosemia is a childhood disease of hereditary nature.[7] 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.[8] Symptoms include ovarian failure, developmental coordination disorder (difficulty speaking correctly and consistently),[9] and neurologic deficits.[8] A single mutation in any of several amino acids can lead to attenuation or deficiency in GALT activity.[10] 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.[8] These two mutations also add new restriction enzyme cut sites, which enable detection by and large-scale population screening with PCR (polymerase chain reaction).[8] 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.[7][11] 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.[12]

Disease Database[edit]

Galactosemia (GALT) Mutation Database

References[edit]

  1. ^ a b "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase". 
  2. ^ 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. 
  3. ^ http://www.mondofacto.com/facts/dictionary?double+displacement+mechanism
  4. ^ a b c d 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. 
  5. ^ http://web.virginia.edu/Heidi/chapter19/chp19frameset.htm
  6. ^ 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. 
  7. ^ a b 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. 
  8. ^ a b c d 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. 
  9. ^ http://www.nidcd.nih.gov/health/voice/apraxia.htm
  10. ^ 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. 
  11. ^ 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. 
  12. ^ http://www.umm.edu/ency/article/000366trt.htm

Further reading[edit]

External links[edit]