Phosphate, metabolism

Human parathyroid hormone (hPTH) is an 84 amino acid polypeptide that functions as a primary regulator of calcium and phosphate metabolism in bones. It stimulates bone formation by osteoblasts, which display high-affinity cell surface receptors for the hormone. PTH also increases intestinal absorption of calcium. 

FIGURE 20-7 Pathways of inositol phosphate metabolism. Note that the metabolism of the second messenger I(1,4,5)P3 is shown to the left of the dashed line, while the interconversions of the higher inositol phosphates are shown to the right of the dashed line. Only the quantitatively major established pathways are depicted. Li+ is known to block the dephosphorylation reactions indicated by the (black) bars. Numbers refer to the following enzymes 1, inositol polyphosphate 5-phosphatase (I) 2, inositol polyphosphate 1-phosphatase 3,I(1,4,5)P3 3-kinase 4, inositol polyphosphate 4-phosphatase 5, inositol polyphosphate 3-phosphatase 6, inositol monophosphate phosphatase 7, I(1,3,4)P3 6-kinase/I(3,4,5,6)P4 1-kinase 8, Ipmk 9, DIPP 10, IP6 kinase 11, Ipk 1 12, MIPP 13, PP-IP5 kinase. 

Li+ causes malformation and affects regeneration in some protozoans, for example Tetrahymenapyriformis [231], by inhibiting both DNA and RNA synthesis by affecting regeneration in Hydra [232], planarians [233], and annelids [234] and by affecting cell signaling mediated by both inositol phosphate metabolism [235] and adenylate cyclase [236] in slime molds. 

Shore, R.F., D.G. Myhill, E.J. Routledge, and A. Wilby. 1995. Impact of an environmentally-realistic intake of cadmium on calcium, magnesium, and phosphate metabolism in bank voles, Clethrionomys glareolus. Arch. Environ. Contam. Toxicol. 29 180-186. 

Activation of neutrophils with PAF occurs through a G-protein-linked receptor, and the subsequent transmembrane signalling involves the stimulation of inositol phosphate metabolism. Within 30 s of addition of PAF (0.01-100 nM), intracellular Ca2+ levels increase and Ca2+ transport from the external medium is enhanced. It seems that phospholipase C-dependent and -independent activation pathways are involved in Ca2+ mobilisation. This indirectly suggests that two receptors may be involved in PAF activation. The first of these is pertussis-toxin-insensitive and may be linked to a... 

These effects of ATP are blocked by pertussis toxin, and so the putative ATP receptor is G-protein linked. ATP addition results in phospholipase C activation, which may be detected as increased inositol phosphate metabolism and subsequent elevations in cytosolic free Ca2+. Purinergic receptors on many types of cells are classified as type Pi or P2. Neutrophils possess P2-type receptors, which are activated by ATP and ADP, and also Pi-type receptors, which are activated by adenosine. Occupancy of P2-type receptors enhances fMet-Leu-Phe-mediated effects, whilst occupancy of Pi-type receptors has the opposing effect. Some pharmacological evidence suggests that the P2-type receptor on neutrophils is distinct from the P2X and P2y subtypes that have been described in other cell types. 

Figure 6.9. Pathways of inositol phosphate metabolism. Ins 1,4,5-P3, generated via the hydrolysis of phosphatidyl 4,5-bisphosphate by phospholipase C, can be metabolised by a kinase (to generate Ins 1,3,4,5-P4) or via a phosphatase (to yield Ins 1,4-P2). These products can be metabolised further to produce inositol, which itself may be sequentially phosphory-lated to regenerate phosphatidylinositol 4,5-bisphosphate.

The D vitamins (Figure 12.7) are a group of compounds that are derived from a steroid nucleus. They are involved in calcium and phosphate metabolism. 

Peptideglycan biosynthesis Metabolism of Complex Lipids Glycerolipid metabolism Inositol phosphate metabolism Sphingophospholipid biosynthesis Phospholipid degradation Sphingoglycolipid metabolism Prostaglandin and leukotriene metabolism... 

Many different pathways, mechanisms, and enzymes are associated with activation. These include dehalogenation, AT-nitrosation of secondary amines, epoxidation, conversion of phosphothionates to phosphate, metabolism of phen-oxyalkanoic acids, oxidation of thioethers, hydrolysis of esters and peroxides. The following is a summary. 

Orthovanadate(V) is a potent inhibitor of many phosphate metabolizing enzymes. In what ways might -mediated enzymes resemble or differ from PO -mediated enzymes N. D. Chasteen, J. K. Grady and C. E. Holloway, Inorg. Chem. 25, 2754 (1986). 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

An additional action of Li" is interruption of the phosphatidylinositide cycle through an inhibitory action on inositol phosphate metabolism. By this mechanism, depletion of membrane inositol and the phosphoinosi-tide-derived second-messenger products diacylglycerol and inositol triphosphate ultimately reduces signaling through receptor systems dependent on the formation of these products. It is presently unclear to what extent inhibition of inositol phosphate metabolism contributes to the therapeutic properties of Li+ in bipolar patients. 

Kato, T., Shioiri, T., Murashita, J., Hamakawa, H., Takahashi, Y., Inubushi, T., and Takahashi, S. (1995) Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol Med 25 557—566. 

A magnetic resonance spectroscopy (MRS) study examined correlates of repetitive violence in 13 mildly mentally retarded individuals and 14 controls (Critch-ley et al., 2000). Concentrations and ratios of N-acetyl aspartate (NAA) and creatine phosphocreatine (Cr-l-PCr) were assayed. The NAA and CR-I-CR concentrations reflect neuronal density and high-energy phosphate metabolism, respectively. Violent patients had lower prefrontal concentrations of NAA and Cr-l-PCr and a lower NAA/Cr-l-PCr ratio in the amyg-dalohippocampal complex than that in controls. Within the violent group, prefrontal NAA concentration correlated with aggression frequency. 

The biological activity of magnesium is manifold. It serves as an indicator for many enzyme reactions, predominantly phosphate metabolism (e.g. as a co-factor in the phosphorylation of glucose). It also plays a part in the regulation of the neuromuscular excitation process. 

Vitamin D. The term vitamin D refers to a group of seco-steroids that possess a common conjugated triene system of double bonds. Vitamin I), (10a) and vitamin D, (10b) are the best-known examples (Fig. 2). Vitamin D (10a) is found primarily in vertebrates, whereas vitamin 11 (10b) is found primarily in plants. The term vitamin is a misnomer. Vitamin I) is a prohormonc that is converted into physiologically active form, primarily 1.25-dihydroxy vitamin D3 (11), by successive hydroxylalions in the liver and kidney. This active form is part of a hormonal system that regulates calcium and phosphate metabolism in the target tissues. 

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