Disease relevance of GK

• We report a 2-year-old boy with Duchenne muscular dystrophy (DMD), glycerol kinase deficiency (GK) and adrenal hypoplasia congenita (AHC) [1].
• Characterisation of a Xp21 microdeletion syndrome in a 2-year-old boy with muscular dystrophy, glycerol kinase deficiency and adrenal hypoplasia congenita [1].
• Molecular studies of the glycerol kinase (GK) and DAX1 genes were performed on four cases of "persistent hypertriglyceridemia" found in an Italian population and on two pediatric cases with high serum glycerol concentration [2].
• Recent studies have shown that the absence of AQP7 expression in fat cells increases glycerol kinase activity, boosting triacylglycerol synthesis and ultimately leading to obesity [3].
• Sequence analysis of 1.5 kb of several overlapping liver cDNA clones predicted a protein with approximately 63% similarity to the E. coli and B. subtilis glycerol kinase genes [4].

Psychiatry related information on GK

• All patients had muscular dystrophy or muscle weakness, mental retardation, congenital adrenal hypoplasia, and glycerol kinase deficiency [5].

High impact information on GK

• Another DMD patient, with additional glycerol kinase deficiency and adrenal hypoplasia, lacks at least 3.3 Mb in the middle region, including marker C7 but not B24, placing C7 closer to DMD [6].
• Genomic DNA from a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia was investigated using cDNA probes for the Duchenne muscular dystrophy (DMD) locus [7].
• Deletion on the X chromosome detected by direct DNA analysis in one of two unrelated boys with glycerol kinase deficiency, adrenal hypoplasia, and Duchenne muscular dystrophy [8].
• Mutations and phenotype in isolated glycerol kinase deficiency [9].
• The crystal structure of the regulatory complex between the glucose enzyme IIA and glycerol kinase has been determined, and the association of the histidine-containing phosphocarrier protein and either the glucose enzyme IIA or the mannitol enzyme IIA have been studied by NMR [10].

Chemical compound and disease context of GK

• Although Alu insertions have been implicated in other diseases, and a closely related AluY element is found as an insert in the C1 inhibitor gene in patients with hereditary angioedema, this is the first case of glycerol kinase deficiency caused by an Alu insertion [11].
• After dissolution of the dried residues in water, the amount of triacylglycerols was quantified using Pseudomonas sp. lipase, glycerol kinase, glycerol-phosphate oxidase, and peroxidase [12].

Biological context of GK

• Two had the glycerol kinase deficiency as part of an Xp21 contiguous gene deletion syndrome-complex form-and three had an isolated form of the enzyme deficiency [13].
• Complex glycerol kinase deficiency: molecular-genetic, cytogenetic, and clinical studies of five Japanese patients [5].
• All the deleted chromosomes also carried a missense mutation at nucleotide 947 of the Xp glycerol kinase (GK) gene resulting in a Thr to Met substitution at codon 278 [14].
• For reliable identification of heterozygotes for isolated glycerol kinase deficiency, knowledge of the specific mutation in the proband is required [13].
• Fine mapping of glycerol kinase deficiency and congenital adrenal hypoplasia within Xp21 on the short arm of the human X chromosome [15].

Anatomical context of GK

• In patient 3, serum transaminases and creatine kinase levels were elevated while the glycerol kinase activity of leukocytes was decreased [16].
• Mitochondrial-bound glycerol kinase in rat brain was examined with reference to factors involved in the binding and significance of the binding in relation to ATP metabolism inside the mitochondria [17].
• RESULTS: The activity of glycerol kinase (GK) in fibroblasts was <10% of reference [18].
• Gyk is a member of a small group of kinases termed ambiquitous enzymes that are found in the cytosol or as membrane-bound enzymes associated with the voltage-dependent anion channel of the mitochondrial outer membrane [19].
• This report describes exciting new data indicating that, although low, the glycerol kinase activity of skeletal muscle is functional [20].

Associations of GK with chemical compounds

• Glycerol kinase (GK) is an enzyme that catalyzes the formation of glycerol 3-phosphate from ATP and glycerol, the rate-limiting step in glycerol utilization [21].
• Adenosine 5'-O-([gamma-18O]gamma-thio)triphosphate chiral at the gamma-phosphorus: stereochemical consequences of reactions catalyzed by pyruvate kinase, glycerol kinase, and hexokinase [22].
• Positive correlation was found between the formation of glycerol 3-phosphate by mitochondrial-bound glycerol kinase and ATP content in mitochondria in experiments using various concentrations of succinate and ADP [17].
• Furthermore, formation of dihydroxyacetone phosphate from glycerol was proved, indicating the involvement of glycerol kinase in glycerol phosphate shuttle in combination with glycerol phosphate dehydrogenase [17].
• 1-Thioglycerol: inhibitor of glycerol kinase activity in vitro and in situ [23].

Physical interactions of GK

• Negative dystrophin staining in muscles of patients with complex glycerol kinase deficiency [24].
• Hexokinase and glycerol kinase interact with porin on the outer surface of the OMM in a manner which provides these enzymes with preferred access to the ATP generated in the mitochondrion [25].

Enzymatic interactions of GK

• The DAX-1 gene was entirely deleted in a 3rd patient as well as in a 4th with the additional feature of glycerol kinase deficiency [26].

Regulatory relationships of GK

• Thiazolidinedione (TZD) has been shown to increase adipose AQP7 and induce glycerol kinase (GlyK) which is nearly absent in adipocytes [27].

Other interactions of GK

• A point mutation in the glycerol kinase gene associated with a deletion in the dystrophin gene in a familial X-linked muscular dystrophy: non-contiguous gene syndrome involving Becker muscular dystrophy and glycerol kinase loci [14].
• Different arseno species are shown to be inhibitors of glycerol kinase, bovine carbonic anhydrase, and also is an effective therapy for acute promyelocytic leukemia, and there has been promising activity noted in other hematologic and solid tumors [28].
• Phosphatidylglycerol is hydrolyzed by phospholipase D (EC 3.1.4.4) to form glycerol, which is subsequently reacted with ATP and NAD+ in the presence of glycerol kinase and glycerol-3-phosphate dehydrogenase to yield NADH [29].
• X-linked adrenal hypoplasia may also be associated with glycerol kinase deficiency and myopathy [30].
• Using polymerase chain reaction and direct DNA sequencing, a novel missense mutation Gly280Ala in the Xp21.3 glycerol kinase gene was found [31].

Analytical, diagnostic and therapeutic context of GK

• To understand the molecular pathogenesis of GKD, we performed microarray analysis on liver mRNA from neonatal glycerol kinase (Gyk) knockout (KO) and wild-type (WT) mice [32].
• To verify these predictions, we developed an RT-PCR system with gene-specific primers that exclusively amplifies the Xp21 glycerol kinase gene transcript [13].
• Prenatal diagnosis of glycerol-kinase deficiency associated with a DNA deletion on the short arm of the X-chromosome [33].
• The Gyk gene was mapped to the mouse X chromosome by both fluorescence in situ hybridization and an interspecies backcross panel, demonstrating conservation of synteny with dmd [19].
• Gene therapy for murine glycerol kinase deficiency: importance of murine ortholog [34].

References