Sugar kinases

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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These are enzymes that catalyse the phosphorylation of sugar molecules. Shared three-dimensional structures identify distinct subfamilies; hexokinases, ribokinases and the eukaryotic mevalonate and phosphomevalonate kinases [2].

Enzymes

Targets of relevance to immunopharmacology are highlighted in blue

ketohexokinase Show summary »« Hide summary

Target Id

3236

Nomenclature

ketohexokinase

Previous and unofficial names

fructokinase

Genes

KHK (Hs), Khk (Mm), Khk (Rn)

Ensembl ID

ENSG00000138030 (Hs), ENSMUSG00000029162 (Mm), ENSRNOG00000008047 (Rn)

UniProtKB AC

P50053 (Hs), P97551 (Rn)

EC number

2.7.1.3

Inhibitors

PF-06835919 pIC₅₀ 8.0 [4]

LY3522348 pIC₅₀ 7.6 – 7.7 [3], 7.4 [3]

Comment

KHK catalyses the first step of metabolism of dietary fructose, converting fructose to fructose-1-phosphate. Two catalytically active isoforms of human KHK have been reported: KHK-C and KHK-A [1]. KHK-C is expressed predominantly in liver, kidney, and small intestine, whilst KHK-A is more widely distributed in other tissues. Inherited KHK deficiency causes essential fructosuria, a benign condition in which the excess fructose is excreted into the urine.

KHK inhibitors are expected to provide clinical benefit by reducing the effects of excess dietary fructose on promoting metabolic dysfunction. In particular KHK inhibitors are proposed to reduce the hepatic manifestations of metabolic syndrome, i.e. hepatic steatosis, fibrosis and inflammation in conditions such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This mechanistic approach may also provide beneficial effects in hyperglycemia and insulin resistance.

References

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1. Asipu A, Hayward BE, O'Reilly J, Bonthron DT. (2003) Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. Diabetes, 52 (9): 2426-32. [PMID:12941785]

2. Bork P, Sander C, Valencia A. (1993) Convergent evolution of similar enzymatic function on different protein folds: the hexokinase, ribokinase, and galactokinase families of sugar kinases. Protein Sci, 2 (1): 31-40. [PMID:8382990]

3. Durham TB, Hao J, Spinazze P, Stack DR, Toth JL, Massey S, Mbofana CT, Johnston RD, Lineswala JP, Wrobleski A et al.. (2023) Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor. J Med Chem, 66 (23): 15960-15976. [PMID:37992274]

4. Futatsugi K, Smith AC, Tu M, Raymer B, Ahn K, Coffey SB, Dowling MS, Fernando DP, Gutierrez JA, Huard K et al.. (2020) Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose. J Med Chem, 63 (22): 13546-13560. [PMID:32910646]

How to cite this family page

Database page citation:

Sugar kinases. Accessed on 27/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1080.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.