1i3k

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MOLECULAR BASIS FOR SEVERE EPIMERASE-DEFICIENCY GALACTOSEMIA: X-RAY STRUCTURE OF THE HUMAN V94M-SUBSTITUTED UDP-GALACTOSE 4-EPIMERASE

Structural highlights

1i3k is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.5Å
Ligands:CL, EDO, MG, NAD, UPG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GALE_HUMAN Defects in GALE are the cause of epimerase-deficiency galactosemia (EDG) [MIM:230350; also known as galactosemia type 3. Clinical features include early-onset cataracts, liver damage, deafness and mental retardation. There are two clinically distinct forms of EDG. (1) A benign, or 'peripheral' form with no detectable GALE activity in red blood cells and characterized by mild symptoms. Some patients may suffer no symptoms beyond raised levels of galactose-1-phosphate in the blood. (2) A much rarer 'generalized' form with undetectable levels of GALE activity in all tissues and resulting in severe features such as restricted growth and mental development.[1] [2] [3] [4] [5] [6] [7] [8]

Function

GALE_HUMAN Catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Galactosemia is an inherited disorder characterized by an inability to metabolize galactose. Although classical galactosemia results from impairment of the second enzyme of the Leloir pathway, namely galactose-1-phosphate uridylyltransferase, alternate forms of the disorder can occur due to either galactokinase or UDP-galactose 4-epimerase deficiencies. One of the more severe cases of epimerase deficiency galactosemia arises from an amino acid substitution at position 94. It has been previously demonstrated that the V94M protein is impaired relative to the wild-type enzyme predominantly at the level of V(max) rather than K(m). To address the molecular consequences the mutation imparts on the three-dimensional architecture of the enzyme, we have solved the structures of the V94M-substituted human epimerase complexed with NADH and UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. In the wild-type enzyme, the hydrophobic side chain of Val(94) packs near the aromatic group of the catalytic Tyr(157) and serves as a molecular "fence" to limit the rotation of the glycosyl portions of the UDP-sugar substrates within the active site. The net effect of the V94M substitution is an opening up of the Ala(93) to Glu(96) surface loop, which allows free rotation of the sugars into nonproductive binding modes.

Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase.,Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM J Biol Chem. 2001 Jun 8;276(23):20617-23. Epub 2001 Mar 7. PMID:11279193[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Timson DJ. Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. FEBS J. 2005 Dec;272(23):6170-7. PMID:16302980 doi:10.1111/j.1742-4658.2005.05017.x
  2. ↑ Maceratesi P, Daude N, Dallapiccola B, Novelli G, Allen R, Okano Y, Reichardt J. Human UDP-galactose 4' epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia. Mol Genet Metab. 1998 Jan;63(1):26-30. PMID:9538513 doi:S1096-7192(97)92645-7
  3. ↑ Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM. Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase. J Biol Chem. 2001 Jun 8;276(23):20617-23. Epub 2001 Mar 7. PMID:11279193 doi:10.1074/jbc.M101304200
  4. ↑ Quimby BB, Alano A, Almashanu S, DeSandro AM, Cowan TM, Fridovich-Keil JL. Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase. Am J Hum Genet. 1997 Sep;61(3):590-8. PMID:9326324 doi:S0002-9297(07)64322-5
  5. ↑ Wohlers TM, Christacos NC, Harreman MT, Fridovich-Keil JL. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia. Am J Hum Genet. 1999 Feb;64(2):462-70. PMID:9973283 doi:S0002-9297(07)61751-0
  6. ↑ Henderson JM, Huguenin SM, Cowan TM, Fridovich-Keil JL. A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia. Clin Genet. 2001 Nov;60(5):350-5. PMID:11903335
  7. ↑ Park HD, Park KU, Kim JQ, Shin CH, Yang SW, Lee DH, Song YH, Song J. The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients. Genet Med. 2005 Nov-Dec;7(9):646-9. PMID:16301867 doi:10.109701.gim.0000194023.27802.2d
  8. ↑ Wasilenko J, Lucas ME, Thoden JB, Holden HM, Fridovich-Keil JL. Functional characterization of the K257R and G319E-hGALE alleles found in patients with ostensibly peripheral epimerase deficiency galactosemia. Mol Genet Metab. 2005 Jan;84(1):32-8. PMID:15639193 doi:S1096-7192(04)00242-2
  9. ↑ Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM. Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase. J Biol Chem. 2001 Jun 8;276(23):20617-23. Epub 2001 Mar 7. PMID:11279193 doi:10.1074/jbc.M101304200

Contents


PDB ID 1i3k

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