The TKFC Ala185Thr variant, reported as ‘null’ for fructose metabolism, is fully active as triokinase

Ribeiro, João Meireles; Costas, Marı́a Jesús; Cabezas, Alicia; Meunier, Brigitte; Onoufriadis, Alexandros; Cameselle, José Carlos

doi:10.1002/1873-3468.14309

Cited by 2 publications

(1 citation statement)

References 19 publications

(52 reference statements)

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“…In contrast, Thr185-TKFC is actually fully active as a triokinase/FMN cyclase, and a yeast growth assay revealed that Ala185-TKFC and Ala185Thr-TKFC overexpression rescued growth in Δdak1 yeast cells. These results suggest that human Thr185-TKFC cannot be considered a ‘null’ variant in terms of triokinase activity [ 86 ].…”

Section: Exogenous Fructose Metabolism and Chrebpmentioning

confidence: 99%

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Iizuka

2023

Nutrients

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Excess fructose intake is associated with obesity, fatty liver, tooth decay, cancer, and cardiovascular diseases. Even after the ingestion of fructose, fructose concentration in the portal blood is never high; fructose is further metabolized in the liver, and the blood fructose concentration is 1/100th of the glucose concentration. It was previously thought that fructose was metabolized in the liver and not in the small intestine, but it has been reported that metabolism in the small intestine also plays an important role in fructose metabolism. Glut5 knockout mice exhibit poor fructose absorption. In addition, endogenous fructose production via the polyol pathway has also received attention; gene deletion of aldose reductase (Ar), ketohexokinase (Khk), and triokinase (Tkfc) has been found to prevent the development of fructose-induced liver lipidosis. Carbohydrate response element-binding protein (Chrebp) regulates the expression of Glut5, Khk, aldolase b, and Tkfc. We review fructose metabolism with a focus on the roles of the glucose-activating transcription factor Chrebp, fructolysis, and the polyol pathway.

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Section: Exogenous Fructose Metabolism and Chrebpmentioning

confidence: 99%

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Iizuka

2023

Nutrients

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Homozygous variant inTKFCabolishing triokinase activities is associated with isolated immunodeficiency

Tremblay-Laganière,

Michaud,

Abourjaili-Bilodeau

et al. 2024

J Med Genet

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BackgroundTriokinase and FMN cyclase (TKFC) is a bifunctional enzyme involved in fructose metabolism. Triokinase catalyses the phosphorylation of fructose-derived glyceraldehyde (GA) and exogenous dihydroxyacetone (DHA), while FMN cyclase generates cyclic FMN. TKFC regulates the antiviral immune response by interacting with IFIH1 (MDA5). Previously reported pathogenic variants inTKFCare associated with either a multisystemic disease or isolated hypotrichosis with loose anagen hairs.MethodsWhole-exome sequencing identified a homozygous novel variant inTKFC(c.1624G>A; p.Gly542Arg) in an individual with a complex primary immunodeficiency disorder. The variant was characterised using enzymatic assays and yeast studies of mutant recombinant proteins.ResultsThe individual presented with chronic active Epstein-Barr virus disease and multiple bacterial and viral infections. Clinical investigations revealed hypogammaglobulinaemia, near absent natural killer cells and decreased memory B cells. Enzymatic assays showed that this variant displayed defective DHA and GA kinase activity while maintaining FMN cyclase activity. An allogenic bone marrow transplantation corrected the patient’s immunodeficiency.ConclusionOur report suggests that TKFC may have a role in the immunological system. The pathological features associated with this variant are possibly linked with DHA/GA kinase inactivation through a yet an unknown mechanism. This report thus adds a possible new pathway of immunometabolism to explore further.

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The TKFC Ala185Thr variant, reported as ‘null’ for fructose metabolism, is fully active as triokinase

Cited by 2 publications

References 19 publications

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Recent Progress on Fructose Metabolism—Chrebp, Fructolysis, and Polyol Pathway

Homozygous variant inTKFCabolishing triokinase activities is associated with isolated immunodeficiency

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