Q14376 (GALE_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
UDP-glucose 4-epimerase
EC=5.1.3.2

Alternative name(s):
Galactowaldenase
UDP-galactose 4-epimerase

Gene names

Name:

GALE

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	348 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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.
Catalytic activity	UDP-glucose = UDP-galactose.
Cofactor	NAD.
Pathway	Carbohydrate metabolism; galactose metabolism.
Subunit structure	Homodimer. Ref.7 Ref.13
Involvement in disease	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. Ref.2 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15
Sequence similarities	Belongs to the sugar epimerase family.
Biophysicochemical properties	Kinetic parameters: KM=69 µM for UDP-galactose (at 37 degrees Celsius and pH 8.8) Ref.11 Ref.13 Vmax=1.22 mmol/min/mg enzyme with UDP-galactose as substrate

Ontologies

Keywords
Biological process	Carbohydrate metabolism Galactose metabolism
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	NAD
Molecular function	Isomerase
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	galactose catabolic process Inferred from direct assay Ref.13. Source: UniProtKB
Cellular component	cytosol Traceable author statement. Source: Reactome
Molecular function	UDP-glucose 4-epimerase activity Inferred from direct assay Ref.13. Source: UniProtKB coenzyme binding Inferred from electronic annotation. Source: InterPro nucleotide binding Inferred from electronic annotation. Source: InterPro protein homodimerization activity Inferred from physical interaction Ref.13. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 348

348

UDP-glucose 4-epimerase

PRO_0000183189

Regions

Nucleotide binding

4 – 35

32

NAD

Sites

Active site

157

1

Proton acceptor

Binding site

132

1

Substrate

Natural variations

Natural variant

25

1

A → V in EDG. Ref.14

VAR_037733

Natural variant

34

1

N → S in EDG; peripheral; nearly normal activity towards UDP-galactose. Ref.9 Ref.12 Ref.13

VAR_002539

Natural variant

40

1

R → C in EDG. Ref.14

VAR_037734

Natural variant

69

1

D → E in EDG. Ref.14

VAR_037735

Natural variant

90

1

G → E in EDG; 800-fold decrease in UDP-galactose epimerization activity. Ref.2 Ref.10 Ref.12 Ref.13
Corresponds to variant rs28940882 [ dbSNP | Ensembl ].

VAR_002540

Natural variant

94

1

V → M in EDG; generalized; 30-fold decrease in UDP-galactose epimerization activity; 2-fold decrease in affinity for UDP-galactose; 24% of normal activity with respect to UDP-N-acetylgalactosamine. Ref.8 Ref.10 Ref.11 Ref.12 Ref.13

VAR_010058

Natural variant

103

1

D → G in EDG; 7-fold decrease in UDP-galactose epimerization activity; very mild decrease in activity towards UDP-N-acetylgalactosamine. Ref.2 Ref.10 Ref.12 Ref.13
Corresponds to variant rs28940883 [ dbSNP | Ensembl ].

VAR_002541

Natural variant

165

1

E → K in EDG. Ref.14

VAR_037736

Natural variant

169

1

R → W in EDG. Ref.14

VAR_037737

Natural variant

180

1

A → V. Ref.1 Ref.9
Corresponds to variant rs3204468 [ dbSNP | Ensembl ].

VAR_002542

Natural variant

183

1

L → P in EDG; peripheral; 3-fold decrease in UDP-galactose epimerization activity. Ref.9 Ref.12 Ref.13

VAR_002543

Natural variant

239

1

R → W in EDG. Ref.14

VAR_037738

Natural variant

257

1

K → R in EDG; 7-fold decrease in UDP-galactose epimerization activity; does not affect affinity for UDP-galactose. Ref.2 Ref.12 Ref.13 Ref.15
Corresponds to variant rs28940884 [ dbSNP | Ensembl ].

VAR_002544

Natural variant

302

1

G → D in EDG. Ref.14

VAR_037739

Natural variant

313

1

L → M in EDG; 6-fold decrease in UDP-galactose epimerization activity; very mild decrease in activity towards UDP-N-acetylgalactosamine. Ref.2 Ref.10 Ref.12 Ref.13
Corresponds to variant rs3180383 [ dbSNP | Ensembl ].

VAR_002545

Natural variant

319

1

G → E in EDG; nearly normal activity towards UDP-galactose; mild impairment under conditions of substrate limitation; may be a polymorphism. Ref.2 Ref.12 Ref.13 Ref.15
Corresponds to variant rs28940885 [ dbSNP | Ensembl ].

VAR_002546

Natural variant

335

1

R → H in EDG; 2-fold decrease in UDP-galactose epimerization activity. Ref.12 Ref.13 Ref.14

VAR_037740

Experimental info

Mutagenesis

132

1

S → A: Loss of activity. Ref.5

Mutagenesis

157

1

Y → F: Loss of activity. Ref.5

Mutagenesis

307

1

C → Y: No effect on activity towards UDP-galactose. Loss of activity towards UDP-N-acetylgalactosamine. Ref.5

Secondary structure

1

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348

Helix Strand Turn

Details...

Beta strand

3 – 8

6

Turn

9 – 11

3

Helix

13 – 24

12

Beta strand

28 – 33

6

Beta strand

36 – 38

3

Beta strand

42 – 46

5

Helix

47 – 56

10

Beta strand

61 – 64

4

Helix

70 – 79

10

Beta strand

82 – 87

6

Helix

94 – 99

6

Helix

101 – 122

22

Beta strand

126 – 130

5

Helix

133 – 136

4

Beta strand

140 – 144

5

Helix

156 – 174

19

Beta strand

179 – 184

6

Beta strand

187 – 189

3

Beta strand

195 – 197

3

Beta strand

206 – 208

3

Helix

209 – 216

8

Beta strand

219 – 221

3

Beta strand

223 – 226

4

Beta strand

230 – 236

7

Beta strand

241 – 243

3

Helix

244 – 259

16

Beta strand

264 – 268

5

Helix

277 – 288

12

Beta strand

294 – 297

4

Beta strand

305 – 307

3

Helix

312 – 318

7

Helix

326 – 339

14

Sequences

	Sequence		Length	Mass (Da)
	Q14376 [UniParc]. Last modified May 10, 2005. Version 2. Checksum: 06FDBF9B1943DF49	FASTA	348	38,282
	10 20 30 40 50 60 MAEKVLVTGG AGYIGSHTVL ELLEAGYLPV VIDNFHNAFR GGGSLPESLR RVQELTGRSV 70 80 90 100 110 120 EFEEMDILDQ GALQRLFKKY SFMAVIHFAG LKAVGESVQK PLDYYRVNLT GTIQLLEIMK 130 140 150 160 170 180 AHGVKNLVFS SSATVYGNPQ YLPLDEAHPT GGCTNPYGKS KFFIEEMIRD LCQADKTWNA 190 200 210 220 230 240 VLLRYFNPTG AHASGCIGED PQGIPNNLMP YVSQVAIGRR EALNVFGNDY DTEDGTGVRD 250 260 270 280 290 300 YIHVVDLAKG HIAALRKLKE QCGCRIYNLG TGTGYSVLQM VQAMEKASGK KIPYKVVARR 310 320 330 340 EGDVAACYAN PSLAQEELGW TAALGLDRMC EDLWRWQKQN PSGFGTQA

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4'-epimerase." Daude N., Gallaher T.K., Zeschnigk M., Starzinski-Powitz A., Petry K.G., Haworth I.S., Reichardt J.K.V. Biochem. Mol. Med. 56:1-7(1995) [PubMed: 8593531] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-180.
[2]	"Human UDP-galactose 4'epimerase (GALE) gene and identification of five missense mutations in patients with epimerase deficiency galactosemia." Maceratesi P., Daude N., Dallapiccola B., Novelli G., Allen R., Okano Y., Reichardt J.K.V. Mol. Genet. Metab. 63:26-30(1998) [PubMed: 9538513] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS EDG GLU-90; GLY-103; ARG-257; MET-313 AND GLU-319.
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cervix and Skin.
[5]	"Determinants of function and substrate specificity in human UDP-galactose 4'-epimerase." Schulz J.M., Watson A.L., Sanders R., Ross K.L., Thoden J.B., Holden H.M., Fridovich-Keil J.L. J. Biol. Chem. 279:32796-32803(2004) [PubMed: 15175331] [Abstract] Cited for: MUTAGENESIS OF SER-132; TYR-157 AND CYS-307.
[6]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed: 21269460] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]	"Crystallographic evidence for Tyr 157 functioning as the active site Proton acceptor in human UDP-galactose 4-epimerase." Thoden J.B., Wohlers T.M., Fridovich-Keil J.L., Holden H.M. Biochemistry 39:5691-5701(2000) [PubMed: 10801319] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEX WITH NAD AND SUBSTRATE, SUBUNIT.
[8]	"Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase." Thoden J.B., Wohlers T.M., Fridovich-Keil J.L., Holden H.M. J. Biol. Chem. 276:20617-20623(2001) [PubMed: 11279193] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF VARIANT EDG MET-94.
[9]	"Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase." Quimby B.B., Alano A., Almashanu S., Desandro A.M., Cowan T.M., Fridovich-Keil J.L. Am. J. Hum. Genet. 61:590-598(1997) [PubMed: 9326324] [Abstract] Cited for: VARIANTS EDG SER-34 AND PRO-183, VARIANT VAL-180.
[10]	"Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia." Wohlers T.M., Christacos N.C., Harreman M.T., Fridovich-Keil J.L. Am. J. Hum. Genet. 64:462-470(1999) [PubMed: 9973283] [Abstract] Cited for: VARIANT EDG MET-94, CHARACTERIZATION OF VARIANTS EDG GLU-90; MET-94; GLY-103 AND MET-313.
[11]	"Studies of the V94M-substituted human UDPgalactose-4-epimerase enzyme associated with generalized epimerase-deficiency galactosaemia." Wohlers T.M., Fridovich-Keil J.L. J. Inherit. Metab. Dis. 23:713-729(2000) [PubMed: 11117433] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, CHARACTERIZATION OF VARIANT MET-94.
[12]	"A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia." Henderson J.M., Huguenin S.M., Cowan T.M., Fridovich-Keil J.L. Clin. Genet. 60:350-355(2001) [PubMed: 11903335] [Abstract] Cited for: VARIANTS EDG SER-34; GLU-90; MET-94; GLY-103; PRO-183; ARG-257; MET-313; GLU-319 AND HIS-335.
[13]	"Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase." Timson D.J. FEBS J. 272:6170-6177(2005) [PubMed: 16302980] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, CHARACTERIZATION OF VARIANTS EDG SER-34; GLU-90; MET-94; GLY-103; PRO-183; ARG-257; MET-313; GLU-319 AND HIS-335, SUBUNIT.
[14]	"The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients." Park H.-D., Park K.U., Kim J.Q., Shin C.H., Yang S.W., Lee D.H., Song Y.-H., Song J. Genet. Med. 7:646-649(2005) [PubMed: 16301867] [Abstract] Cited for: VARIANTS EDG VAL-25; CYS-40; GLU-69; LYS-165; TRP-169; TRP-239; ASP-302 AND HIS-335.
[15]	"Functional characterization of the K257R and G319E-hGALE alleles found in patients with ostensibly peripheral epimerase deficiency galactosemia." Wasilenko J., Lucas M.E., Thoden J.B., Holden H.M., Fridovich-Keil J.L. Mol. Genet. Metab. 84:32-38(2005) [PubMed: 15639193] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS EDG ARG-257 AND GLU-319.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L41668 mRNA. Translation: AAB86498.1.
AF022382 Genomic DNA. Translation: AAC39645.1.
AL031295 Genomic DNA. Translation: CAB40159.1.
BC001273 mRNA. Translation: AAH01273.1.
BC050685 mRNA. Translation: AAH50685.2.

IPI

IPI00553131.

RefSeq

NP_000394.2. NM_000403.3.
NP_001008217.1. NM_001008216.1.
NP_001121093.1. NM_001127621.1.

UniGene

Hs.632380.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1EK5	X-ray	1.80	A	1-348	[»]
1EK6	X-ray	1.50	A/B	1-348	[»]
1HZJ	X-ray	1.50	A/B	1-348	[»]
1I3K	X-ray	1.50	A/B	1-348	[»]
1I3L	X-ray	1.50	A/B	1-348	[»]
1I3M	X-ray	1.50	A/B	1-348	[»]
1I3N	X-ray	1.50	A/B	1-348	[»]

ProteinModelPortal

Q14376.

SMR

Q14376. Positions 1-346.

ModBase

Search...

Protein-protein interaction databases

IntAct

Q14376. 2 interactions.

STRING

Q14376.

Polymorphism databases

DMDM

68056598.

Proteomic databases

PRIDE

Q14376.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000313298; ENSP00000313026; ENSG00000117308.
ENST00000374497; ENSP00000363621; ENSG00000117308.
ENST00000426964; ENSP00000397709; ENSG00000117308.

GeneID

2582.

KEGG

hsa:2582.

UCSC

uc001bhv.1. human.

Organism-specific databases

CTD

2582.

GeneCards

GC01M024122.

H-InvDB

HIX0199871.

HGNC

HGNC:4116. GALE.

HPA

HPA007340.

MIM

230350. phenotype.
606953. gene.

neXtProt

NX_Q14376.

Orphanet

352. Galactosemia.

PharmGKB

PA28531.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG07657.

HOGENOM

HBG755066.

HOVERGEN

HBG001396.

InParanoid

Q14376.

OMA

TGRSVEF.

OrthoDB

EOG4B5P5D.

PhylomeDB

Q14376.

Enzyme and pathway databases

BioCyc

MetaCyc:MONOMER-13184.

Reactome

REACT_474. Metabolism of carbohydrates.

Gene expression databases

ArrayExpress

Q14376.

Bgee

Q14376.

CleanEx

HS_GALE.

Genevestigator

Q14376.

GermOnline

ENSG00000117308. Homo sapiens.

Family and domain databases

InterPro

IPR001509. Epimerase_deHydtase.
IPR005886. GalE.
IPR016040. NAD(P)-bd_dom.
IPR008089. Nuc_sugar_epim.
[Graphical view]

Gene3D

G3DSA:3.40.50.720. NAD(P)-bd. 1 hit.

KO

K01784.

PANTHER

PTHR10366:SF39. GalE. 1 hit.

Pfam

PF01370. Epimerase. 1 hit.
[Graphical view]

PRINTS

PR01713. NUCEPIMERASE.

TIGRFAMs

TIGR01179. GalE. 1 hit.

ProtoNet

Search...

Other

NextBio

10213.

SOURCE

Search...

Entry information

Entry name

GALE_HUMAN

Accession

Primary (citable) accession number: Q14376
Secondary accession number(s): Q86W41, Q9BVE3, Q9UJB4

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	May 10, 2005
Last modified:	January 25, 2012
This is version 125 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.