Summary: Galactose-1-phosphate uridyl transferase, N-terminal domain
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Galactose-1-phosphate uridylyltransferase Edit Wikipedia article
|Galactose-1-phosphate uridyl transferase, N-terminal domain|
|Galactose-1-phosphate uridyl transferase, C-terminal domain|
structure of nucleotidyltransferase complexed with 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.
GALT catalyzes the second reaction of the Leloir pathway of galactose metabolism through ping pong bi-bi kinetics with a double displacement mechanism. 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. 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.
- UDP-glucose + E-His ⇌ Glucose-1-phosphate + E-His-UMP
- Galactose-1-phosphate + E-His-UMP ⇌ UDP-galactose + E-His
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. 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.
Deficiency of GALT causes classic galactosemia. Galactosemia is an autosomal recessive inherited disorder detectable in newborns and childhood. 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. Symptoms include ovarian failure, developmental coordination disorder (difficulty speaking correctly and consistently), and neurologic deficits. A single mutation in any of several base pairs can lead to deficiency in GALT activity. 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. These two mutations also add new restriction enzyme cut sites, which enable detection by and large-scale population screening with PCR (polymerase chain reaction). 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. 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.
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Entrez Gene: GALT galactose-1-phosphate uridylyltransferase".
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 . PMID 12552079.
- Lai K, Elsas LJ, Wierenga KJ (November 2009). "Galactose toxicity in animals". IUBMB Life. 61 (11): 1063–74. doi:10.1002/iub.262. PMC . PMID 19859980.
- 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 . 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 . 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 . 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 . 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 . 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, N-terminal domain Provide feedback
SCOP reports fold duplication with C-terminal domain. Both involved in Zn and Fe binding.
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 IPR005849
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
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||UDP-glucose:hexose-1-phosphate uridylyltransferase activity (GO:0008108)|
|Biological process||galactose metabolic process (GO:0006012)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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The HIT superfamily are a superfamily of nucleotide hydrolases and transferases, which act on the alpha-phosphate of ribonucleotides .
The clan contains the following 8 members:CDH CwfJ_C_1 DcpS_C DUF4921 DUF4931 GalP_UDP_tr_C GalP_UDP_transf HIT
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Author:||Finn RD, Bateman A, Griffiths-Jones SR|
|Number in seed:||78|
|Number in full:||2540|
|Average length of the domain:||172.00 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||45.62 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||21|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 3 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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_transf domain has been found. There are 24 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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