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12  structures 896  species 3  interactions 957  sequences 10  architectures

Family: GalP_UDP_tr_C (PF02744)

Summary: Galactose-1-phosphate uridyl transferase, C-terminal domain

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This is the Wikipedia entry entitled "Galactose-1-phosphate uridylyltransferase". More...

Galactose-1-phosphate uridylyltransferase Edit Wikipedia article

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_001302511
RefSeq (protein) NP_000146 NP_001289440
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

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

Structural studies

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

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

Galactosemia (GALT) Mutation Database

References

  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

  • 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. 

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Galactose-1-phosphate uridyl transferase, C-terminal domain Provide feedback

SCOP reports fold duplication with N-terminal domain. Both involved in Zn and Fe binding.

Literature references

  1. Wedekind JE, Frey PA, Rayment I; , Biochemistry 1995;34:11049-11061.: Three-dimensional structure of galactose-1-phosphate uridylyltransferase from Escherichia coli at 1.8 A resolution. PUBMED:7669762 EPMC:7669762


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR005850

Galactose-1-phosphate uridyl transferase catalyses the conversion of UDP-glucose and alpha-D-galactose 1-phosphate to alpha-D-glucose 1-phosphate and UDP-galactose during galactose metabolism. The enzyme is present in prokaryotes and eukaryotes. Defects in GalT in humans is the cause of galactosemia, an inherited disorder of galactose metabolism that leads to jaundice, cataracts and mental retardation.

This domain describes the C-terminal of Galactose-1-phosphate uridyl transferase. SCOP reports fold duplication of the C-terminal with the N-terminal domain. Both are involved in Zn and Fe binding

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan HIT (CL0265), which has the following description:

The HIT superfamily are a superfamily of nucleotide hydrolases and transferases, which act on the alpha-phosphate of ribonucleotides [1].

The clan contains the following 8 members:

CDH CwfJ_C_1 DcpS_C DUF4921 DUF4931 GalP_UDP_tr_C GalP_UDP_transf HIT

Alignments

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(8)
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(957)
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(4579)
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Meta
(238)
RP15
(228)
RP35
(610)
RP55
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RP75
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(8)
Full
(957)
Representative proteomes UniProt
(4579)
NCBI
(7185)
Meta
(238)
RP15
(228)
RP35
(610)
RP55
(932)
RP75
(1282)
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  Seed
(8)
Full
(957)
Representative proteomes UniProt
(4579)
NCBI
(7185)
Meta
(238)
RP15
(228)
RP35
(610)
RP55
(932)
RP75
(1282)
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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: GalP_UDP_trans_C;
Type: Domain
Author: Finn RD, Bateman A, Griffiths-Jones SR
Number in seed: 8
Number in full: 957
Average length of the domain: 172.90 aa
Average identity of full alignment: 28 %
Average coverage of the sequence by the domain: 43.29 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 29.2 29.2
Trusted cut-off 29.2 29.2
Noise cut-off 29.0 29.1
Model length: 167
Family (HMM) version: 14
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Interactions

There are 3 interactions for this family. More...

GalP_UDP_transf GalP_UDP_transf GalP_UDP_tr_C

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GalP_UDP_tr_C domain has been found. There are 12 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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