Galactokinase

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Galactokinase 1
Chr. 17 q23-q25
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StructuresSwiss-model
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Galactokinase 2
Identifiers
SymbolGALK2
Chr. 15 [1]
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Galactokinase is an

humans.[8][9]

Structure

Galactokinase is composed of two domains separated by a large cleft. The two regions are known as the N- and C-terminal domains, and the

alpha-helices, and the C-terminal domain is characterized by two layers of anti-parallel beta-sheets and six alpha-helices.[8] Galactokinase does not belong to the sugar kinase family, but rather to a class of ATP-dependent enzymes known as the GHMP superfamily.[10] GHMP is an abbreviation referring to its original members: galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase. Members of the GHMP superfamily have great three-dimensional similarity despite only ten to 20% sequence identity. These enzymes contain three well-conserved motifs (I, II, and III), the second of which is involved in nucleotide binding and has the sequence Pro-X-X-X-Gly-Leu-X-Ser-Ser-Ala.[11]

Sugar specificity

Galactokinases across different species display a great diversity of

S. cerevisiae, on the other hand, is highly specific for D-galactose and cannot phosphorylate glucose, mannose, arabinose, fucose, lactose, galactitol, or 2-deoxy-D-galactose.[3][4] Moreover, the kinetic properties of galactokinase also differ across species.[8] The sugar specificity of galactokinases from different sources has been dramatically expanded through directed evolution[15] and structure-based protein engineering.[16][17] The corresponding broadly permissive sugar anomeric kinases serve as a cornerstone for in vitro and in vivo glycorandomization.[18][19][20]

Mechanism

Recently, the roles of

anionic form and has also been proven to be essential to galactokinase function in point mutation experiments.[9] Both the aspartic acid and arginine active site residues are highly conserved among galactokinases.[8]

The likely galactokinase mechanism.[9] The aspartate residue is stabilized in its anionic form by a nearby arginine residue.
Crystal structure of galactokinase active site from Lactococcus lactis.[11] Galactokinase is shown in green, phosphate in orange, and the residues responsible for binding the sugar ligand are shown in magenta: Arg-36, Glu-42, Asp-45, Asp-183, and Tyr-233. Arg-36 and Asp-183 of Lactococcus lactis galactokinase are analogous to Arg-37 and Asp-186 in human galactokinase. (From PDB: 1PIE​)

Biological function

The Leloir pathway catalyzes the conversion of galactose to glucose. Galactose is found in

glycolipids. Three enzymes are required in the Leloir pathway: galactokinase, galactose-1-phosphate uridylyltransferase, and UDP-galactose 4-epimerase. Galactokinase catalyzes the first committed step of galactose catabolism, forming galactose 1-phosphate.[2][21]

Disease relevance

lens cells of the human eye, aldose reductase converts galactose to galactitol. As galactose is not being catabolized to glucose due to a galactokinase mutation, galactitol accumulates. This galactitol gradient across the lens cell membrane triggers the osmotic uptake of water, and the swelling and eventual apoptosis of lens cells ensues.[22]

References

  1. ^ "galactokinase". Medical Dictionary. Retrieved 2013-01-26.
  2. ^
    S2CID 13857006
    .
  3. ^
    PMID 107173
    .
  4. ^
    PMID 16603548
    .
  5. PMID 15003454
    .
  6. PMID 182286
    .
  7. PMID 6617655
    .
  8. ^
    S2CID 7293337
    .
  9. ^
    PMID 21474160
    .
  10. PMID 20696150
    .
  11. ^
    PMID 12796487
    .
  12. PMID 12816414
    .
  13. PMID 14596685
    .
  14. PMID 5665881
    .
  15. PMID 14612558
    .
  16. PMID 15975511
    .
  17. PMID 18678278
    .
  18. PMID 16309329
    .
  19. PMID 20886903
    .
  20. PMID 21901218
    .
  21. PMID 12923184
    .
  22. PMID 12694189
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Galactokinase&oldid=1215352004"