Molecular Structure of Human Galactokinase

Thoden, James B.; Timson, David J.; Reece, Richard J.; Holden, Hazel M.

doi:10.1074/jbc.m412916200

Cited by 100 publications

(95 citation statements)

References 43 publications

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“…The selectivity of the GalAK for the ␣-anomeric configuration of monosaccharides is not unique to this kinase. The GalK from human (23,27), bacteria (24), and yeast (22), as well as the Arabidopsis GalK, are also selective for the ␣-configuration of the sugar (see Fig. 4B and supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The motif, PGRVNLIG(AE)-HXDY, at the N-terminal region of the protein, is involved in sugar binding. The motif GL(GS)SSA, which is located ϳ100 aa downstream of the N-terminal motif, is involved in binding the ␣-and ␤-phosphate groups of ADP (21), whereas the motif, GAGXG, located at the C-terminal region is involved in catalysis and transfer of the ␥ phosphate to the sugar (23).…”

Section: Identification Cloning and Characterization Of Arabidopsismentioning

confidence: 99%

“…GalK from E. coli, yeast, human, and Pyrococcus furiosus (21)(22)(23)(24) has conserved folds and amino acid domains. GalK is a member of the GHMP superfamily that includes galactokinase (G), homoserine kinase (H), mevalonate kinase (M), and phosphomevalonate kinase (P).…”

Section: Identification Cloning and Characterization Of Arabidopsismentioning

confidence: 99%

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Identification of Galacturonic Acid-1-phosphate Kinase, a New Member of the GHMP Kinase Superfamily in Plants, and Comparison with Galactose-1-phosphate Kinase

Yang

Bar-Peled²,

Gebhart

et al. 2009

Journal of Biological Chemistry

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The process of salvaging sugars released from extracellular matrix, during plant cell growth and development, is not well understood, and many molecular components remain to be identified. Here we identify and functionally characterize a unique Arabidopsis gene encoding an ␣-D-galacturonic acid-1-phosphate kinase (GalAK) and compare it with galactokinase. The GalAK gene appeared to be expressed in all tissues implicating that glycose salvage is a common catabolic pathway. GalAK catalyzes the ATP-dependent conversion of ␣-D-galacturonic acid (D-GalA) to ␣-D-galacturonic acid-1-phosphate (GalA-1-P). This sugar phosphate is then converted to UDPGalA by a UDP-sugar pyrophosphorylase as determined by a real-time 1 H NMR-based assay. GalAK is a distinct member of the GHMP kinase family that includes galactokinase (G), homoserine kinase (H), mevalonate kinase (M), and phosphomevalonate kinase (P). Although these kinases have conserved motifs for sugar binding, nucleotide binding, and catalysis, they do have subtle difference. For example, GalAK has an additional domain near the sugar-binding motif. Using site-directed mutagenesis we established that mutation in A368S reduces phosphorylation activity by 40%; A41E mutation completely abolishes GalAK activity; Y250F alters sugar specificity and allows phosphorylation of D-glucuronic acid, the 4-epimer of GalA. Unlike many plant genes that undergo duplication, GalAK occurs as a single copy gene in vascular plants. We suggest that GalAK generates GalA-1-P from the salvaged GalA that is released during growth-dependent cell wall restructuring, or from storage tissue. The GalA-1-P itself is then available for use in the formation of UDP-GalA required for glycan synthesis.3 is a quantitatively major glycose present in numerous plant polysaccharides including pectins and arabinogalactan proteins (1, 2). The synthesis of these polysaccharides requires a large number of glycosyltransferases and diverse nucleotide-sugar (NDP-sugar) donors (1, 3). Some of these NDP-sugars are formed by interconversion of pre-existing NDP-sugars and by salvage pathways. For example, the main pathway for UDP-GalA formation is the 4-epimerization of UDP-GlcA, a reaction catalyzed by UDP-GlcA 4-epimerase (4 -6). However, in ripening Fragaria fruit D-GalA is incorporated into pectin (7). It is likely that a sugar kinase converts the D-GalA to GalA-1-P (8), which is then converted to UDP-GalA by a nonspecific UDP-sugar pyrophosphorylase (9). Myo-inositol may also be a source of GalA for polysaccharide biosynthesis (10).Galacturonic acid is likely to be generated by enzyme-catalyzed hydrolysis of pectic polysaccharides in plant tissues. Polysaccharide hydrolase activities are present in germinating seeds (11, 12), in germinating and elongating pollen (13-15), and in ripening fruit (14). Thus, monosaccharide salvage pathways may be required for normal plant growth and development.Numerous sugar-1-P kinases, including D-Gal-1-P kinase (16), L-Ara-1-P kinase (17), and L-Fuc-1-P kinase (18), have been describ...

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Section: Discussionmentioning

confidence: 99%

Section: Identification Cloning and Characterization Of Arabidopsismentioning

confidence: 99%

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Identification of Galacturonic Acid-1-phosphate Kinase, a New Member of the GHMP Kinase Superfamily in Plants, and Comparison with Galactose-1-phosphate Kinase

Yang

Bar-Peled²,

Gebhart

et al. 2009

Journal of Biological Chemistry

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“…This enzyme belongs to the galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase superfamily, and catalyzes the MgATP-dependent phosphorylation of D-galactose to form Gal-1-P. 14 16 The most severe phenotype is associated with an insoluble enzyme, while milder phenotypes are characterized by soluble enzyme with impaired catalytic function.…”

Section: Galactokinasementioning

confidence: 99%

“…GALK and GALE activity are traditionally measured by monitoring production of 14 C-Gal-1-P and 14 C-UDP-glucose from 14 C-galactose and 14 C-UDP-galactose respectively. Weak cation exchange materials, such as diethylaminoethyl cellulose (DEAE), are used for separation of radiolabeled substrates and products.…”

Section: Galk and Gale Assaysmentioning

confidence: 99%

Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)

Pasquali

Coffee

2018

Genetics in Medicine

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Molecular Genetics of Galactosaemia

Lai

Mao

2012

Encyclopedia of Life Sciences

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The three different enzymes of galactose metabolism (galactokinase, galactose‐1‐phosphate uridyltransferase, UDP‐galactose‐4‐epimerase) can be impaired by genetic alterations, leading to three different forms of the genetic disease, galactosaemia. Their clinical outcome can vary from very mild to lethal depending on the enzyme involved, and on the respective gene mutations, but a clear‐cut correlation between genotype and phenotype of patients is not yet known. Understanding the molecular genetics of galactosaemia is essential to correlate the genotype of the patients to their phenotype, and eventually to their clinical outcome. The prediction of the effects of genetic alterations on enzyme structure and functions is just the first step of the long journey towards the final scope: to render clinicians and scientific community the tools to predict the effect of a galactosaemia‐linked mutation on the future quality of life of an affected newborn, in order to provide the best personalised solutions for the treatment. Key Concepts: Disorders in galactose metabolism in humans caused by hereditary deficiencies of the enzymes in the Leloir pathway can lead to severe and potentially lethal diseases called galactosaemia. Depending on the specific enzyme that is deficient, three types of galactosaemia (Type I, II and III) with varying severity can occur. Newborn screening programmes for galactosaemia are implemented in many developed countries to prevent acute lethality in the affected neonates. The genes encoding the enzymes associated with all types of galactosaemia have been isolated, allowing the determination of the deleterious changes leading to the diseases. Many of the variations seen in the GAL genes are private in nature, although specific changes are prevalent in different ethnic populations.

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Molecular Structure of Human Galactokinase

Cited by 100 publications

References 43 publications

Identification of Galacturonic Acid-1-phosphate Kinase, a New Member of the GHMP Kinase Superfamily in Plants, and Comparison with Galactose-1-phosphate Kinase

Identification of Galacturonic Acid-1-phosphate Kinase, a New Member of the GHMP Kinase Superfamily in Plants, and Comparison with Galactose-1-phosphate Kinase

Laboratory diagnosis of galactosemia: a technical standard and guideline of the American College of Medical Genetics and Genomics (ACMG)

Molecular Genetics of Galactosaemia

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