Hepatic fructokinase

ketohexokinase (fructokinase)
Ketohexokinase homodimer, Human
Identifiers
Symbol	KHK
NCBI gene	3795
HGNC	6315
OMIM	229800
RefSeq	NM_006488
UniProt	P50053
Other data
EC number	2.7.1.3
Locus	Chr. 2 p23.3-23.2
Search for Structures Swiss-model Domains InterPro

Ketohexokinase
Identifiers
EC no.	2.7.1.3
CAS no.	9030-50-6
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Hepatic fructokinase (or ketohexokinase) is an enzyme that catalyzes the phosphorylation of fructose to produce fructose-1-phosphate.

ATP +  ${\displaystyle \longrightarrow }$ ADP +

ATP + D-fructose → ADP + D-fructose-1-phosphate ^[1]

Isoforms

In humans, ketohexokinase is encoded by the KHK gene, which produces two isoforms, KHK-A and KHK-C, through alternative splicing.

• KHK-C is primarily expressed in the liver, kidney, and intestine. It has a high affinity for fructose (low K_m) and is responsible for the majority of fructose metabolism.
• KHK-A is ubiquitously expressed in many tissues at low levels. It has a significantly lower affinity for fructose (high K_m) compared to the C isoform. ^[2]

Pathology

A deficiency is associated with essential fructosuria.

Physiological Significance

The "Fructose Survival Hypothesis" proposes that ketohexokinase activity plays a central role in energy storage and survival during periods of food scarcity. According to this model, the rapid phosphorylation of fructose by KHK-C causes a transient depletion of hepatocellular ATP and the generation of uric acid. This metabolic stress signal is hypothesized to shift metabolism towards mitochondrial oxidative stress and fat accumulation. While this mechanism potentially aids survival in resource-poor environments, researchers suggest it contributes to metabolic syndrome and insulin resistance in modern dietary contexts. ^{[3] [4]}

Inhibitors

Several natural and synthetic compounds have been studied as inhibitors of ketohexokinase (KHK) to modulate fructose metabolism.

• Luteolin: Preclinical studies have identified the flavonoid luteolin as a compound capable of inhibiting fructokinase activity in vitro. In murine models, blockade of fructokinase has been shown to protect against fructose-induced kidney injury, supporting the role of KHK-dependent fructose metabolism in renal pathology. ^[5]
• Osthole: Osthole, a coumarin derivative found in several plant species, was identified as an inhibitor of ketohexokinase through bioactivity-guided screening of botanical compounds. Enzyme assays demonstrated inhibition of KHK activity, with effects confirmed in preclinical metabolic models. ^[6]

References

1. Bais R, James HM, Rofe AM, Conyers RA (1985). "The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol". Biochem. J. 230 (1): 53–60. doi:10.1042/bj2300053. PMC   1152585 . PMID   2996495.
2. Diggle CP, Shires M, Leitch D, Brooke D, Carr IM, Markham AF, Hayward BE, Asipu A, Bonthron DT (2009). "Ketohexokinase: Expression and Localization of the Principal Fructose-metabolizing Enzyme". Journal of Histochemistry & Cytochemistry. 57 (8): 763–774. doi:10.1369/jhc.2009.953190. PMC   2713076 . PMID   19365088.
3. Johnson RJ, Lanaspa MA, Sanchez-Lozada LG, Tolan D, Nakagawa T, Ishimoto T, Andres-Hernando A, Rodriguez-Iturbe B, Stenvinkel P (2023). "The fructose survival hypothesis for obesity". Philosophical Transactions of the Royal Society B: Biological Sciences. 378 (1885) 20220230. doi:10.1098/rstb.2022.0230. PMC   10363162 . PMID   37482773.
4. Johnson RJ, Stenvinkel P, Andrews P, et al. (2020). "Fructose metabolism as a common evolutionary pathway of survival associated with climate change, food shortage and droughts". Journal of Internal Medicine. 287 (3): 252–262. doi:10.1111/joim.12993. PMC   10917390 . PMID   31621967.
5. Andres-Hernando A, Li N, Cicerchi C, et al. (2017). "Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice". Nature Communications. 8 14181. Bibcode:2017NatCo...814181A. doi:10.1038/ncomms14181. PMC   5316807 . PMID   28194018.
6. Le MT, Lanaspa MA, Cicerchi CM, et al. (2016). "Bioactivity-Guided Identification of Botanical Inhibitors of Ketohexokinase". PLOS ONE. 11 (6) e0157458. Bibcode:2016PLoSO..1157458L. doi: 10.1371/journal.pone.0157458 . PMC   4913896 . PMID   27322374.

External links

• Hepatic+fructokinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)