Key enzyme in myo-inositol biosynthesis pathway that catalyzes the conversion of glucose 6-phosphate to 1-myo-inositol 1-phosphate in a NAD-dependent manner. Rate-limiting enzyme in the synthesis of all inositol-containing compounds.
We have cloned, sequenced, and expressed a human cDNA encoding 1-d-myo-inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted d-glucose 6-phosphate to 1-d-myo-inositol 3-phosphate, the rate-limiting step for de novo inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37 degrees C and exhibited K(m) values of 0.57 mm and 8 microm for glucose 6-phosphate and NAD(+), respectively. NH(4)(+) and K(+) were better activators than other cations tested (Na(+), Li(+), Mg(2+), Mn(2+)), and Zn(2+) strongly inhibited activity. Expression of the protein in the yeast ino1Delta mutant lacking MIP synthase (ino1Delta/hINO1) complemented the inositol auxotrophy of the mutant and led to inositol excretion. MIP synthase activity and intracellular inositol were decreased about 35 and 25%, respectively, when ino1Delta/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mm). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in inositol biosynthesis underscores the power of the yeast model in studies of this disorder.
Catalysis of the reaction: D-glucose 6-phosphate = 1D-myo-inositol 3-phosphate. This reaction requires NAD, which dehydrogenates the CHOH group to CO at C-5 of the glucose 6-phosphate, making C-6 into an active methylene, able to condense with the aldehyde at C-1. Finally, the enzyme-bound NADH reconverts C-5 into the CHOH form.
Interacting selectively and non-covalently with a nucleotide, any compound consisting of a nucleoside that is esterified with (ortho)phosphate or an oligophosphate at any hydroxyl group on the ribose or deoxyribose.
The chemical reactions and pathways resulting in the formation of inositol, 1,2,3,4,5,6-cyclohexanehexol, a growth factor for animals and microorganisms.
We have cloned, sequenced, and expressed a human cDNA encoding 1-d-myo-inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted d-glucose 6-phosphate to 1-d-myo-inositol 3-phosphate, the rate-limiting step for de novo inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37 degrees C and exhibited K(m) values of 0.57 mm and 8 microm for glucose 6-phosphate and NAD(+), respectively. NH(4)(+) and K(+) were better activators than other cations tested (Na(+), Li(+), Mg(2+), Mn(2+)), and Zn(2+) strongly inhibited activity. Expression of the protein in the yeast ino1Delta mutant lacking MIP synthase (ino1Delta/hINO1) complemented the inositol auxotrophy of the mutant and led to inositol excretion. MIP synthase activity and intracellular inositol were decreased about 35 and 25%, respectively, when ino1Delta/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mm). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in inositol biosynthesis underscores the power of the yeast model in studies of this disorder.
We have cloned, sequenced, and expressed a human cDNA encoding 1-d-myo-inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted d-glucose 6-phosphate to 1-d-myo-inositol 3-phosphate, the rate-limiting step for de novo inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37 degrees C and exhibited K(m) values of 0.57 mm and 8 microm for glucose 6-phosphate and NAD(+), respectively. NH(4)(+) and K(+) were better activators than other cations tested (Na(+), Li(+), Mg(2+), Mn(2+)), and Zn(2+) strongly inhibited activity. Expression of the protein in the yeast ino1Delta mutant lacking MIP synthase (ino1Delta/hINO1) complemented the inositol auxotrophy of the mutant and led to inositol excretion. MIP synthase activity and intracellular inositol were decreased about 35 and 25%, respectively, when ino1Delta/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mm). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in inositol biosynthesis underscores the power of the yeast model in studies of this disorder.
OBJECTIVES: Alternative splicing allows the production of multiple gene products with different functions from a given sequence, affecting cellular function control. Tissue-specific splicing is most prevalent in the brain. We therefore investigate whether splice variants contribute to complex psychiatric disorders. A database search suggested that the myo-inositol-1-phosphate (MIP) synthase gene, possibly involved in pathophysiology of bipolar disorder, has splice variants. METHODS: Human RNA was purified from lymphocytes and postmortem brain. MIP synthase alternative splice variants were amplified using reverse transcription-polymerase chain reaction. RESULTS: The bioinformatics finding was confirmed in both tissues. No difference in lymphocyte MIP synthase mRNA splice-variant levels was found between bipolar patients and controls. However, patients with family history of a major psychiatric disorder had significantly higher levels of the variant lacking exons 3 and 4 versus patients with no family history and controls. CONCLUSIONS: As alternative splicing may be a mechanism by which the approximately 30,000 genes are amplified in mammalian brain, further studies with other candidate genes for psychiatric disorders are needed.
We have recently shown that valproate (VPA) decreases intracellular concentrations of inositol, like lithium but via a different mechanism, namely by inhibiting myo-inositol-1-phosphate (MIP) synthase. Valnoctamide (VCD) and valrocemide (VGD) are VPA derivatives which are anticonvulsants and have been shown in animal models to be significantly less teratogenic than VPA. We now show that 1 mM of either VCD or VGD drastically inhibits human brain crude homogenate MIP synthase activity. We studied the mechanism of the effect of VCD and found that it reduced the enzyme activity by an apparent competitive mode of inhibition at concentrations within the therapeutic range of VPA(Ki = 0.18 mM). We studied the behavioral effect of VGD and found that both lithium and VGD attenuated amphetamine-induced increase in rearing. These data support clinical study of these VPA-derivatives in bipolar disorder.
Protein involved in the synthesis of inositol, a cyclic hexahydric alcohol. It occurs in various forms, of which myo-inositol, a constituent of phospholipids, is the most important.
Protein involved in the synthesis of lipids, a diverse class of compounds which are insoluble in water but soluble in organic solvents. They include fats, oils, triacylglycerols, fatty acids, glycolipids, phospholipids and steroids.
Protein involved in the biochemical reactions of lipids. Lipids are a diverse class of compounds which are insoluble in water but soluble in organic solvents. They include fats, oils, triacylglycerols, fatty acids, glycolipids, phospholipids and steroids.
Protein involved in the synthesis of phospholipids, the major lipid component of most cellular membranes. Phospholipids are usually composed of two fatty acid chains esterified to two of the carbons of glycerol phosphate, the phosphate being esterified to a hydroxyl group of another hydrophilic compound, such as choline, ethanolamine or serine.
Protein involved in the metabolism of phospholipids, the major lipid component of most cellular membranes. Phospholipids are usually composed of two fatty acid chains esterified to two of the carbons of glycerol phosphate, the phosphate being esterified to a hydroxyl group of another hydrophilic compound, such as choline, ethanolamine or serine.
Enzyme that catalyzes the 1,1-, 1,2- or 1,3-hydrogen shift. The 1,1- hydrogen shift is an inversion at an asymmetric carbon center (racemases, epimerases). The 1,2-hydrogen shift involved a hydrogen transfer between two adjacent carbon atoms, one undergoing oxidation, the other reduction (aldose-ketose isomerases). The 1,3-hydrogen shifts are allylic or azaallylic (when nitrogen is one of the three atoms) isomerizations.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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