Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Esters of succinic acid stimulate insulin secretion from pancreatic beta-cells. Using collagenase-isolated rat islets, the transduction mechanisms involved were investigated. In freshly isolated perifused islets, monomethyl succinate (MMSucc), in the presence of basal (2.75 mM) glucose, stimulated insulin release in a biphasic pattern. This secretory response was dependent on extracellular calcium movement into the beta-cell, since the calcium channel blocker nitrendipine (5 microM) abolished it. The glucokinase inhibitor mannoheptulose (20 mM) had no effect on its secretory action, while the protein kinase-C inhibitor staurosporine (20 nM) reduced secretion to MMSucc. In addition, while ineffective alone, the diacylglycerol kinase inhibitor monooleoylglycerol (25 microM) potentiated MMSucc-induced insulin release. A similarly amplified response occurred in the presence of forskolin (0.25 microM), a compound that elevates islet cAMP levels. The sodium salt of succinic acid (20 mM) had no effect on insulin release in the presence or absence of forskolin. Prior treatment with MMSucc in the presence of 2.75 mM glucose sensitized islets to the usually weak insulin secretory effect of 7.5 mM glucose. Other groups of islets were incubated for 2 h with myo-[2-3H]inositol to label their phosphoinositide pools. These islets were subsequently stimulated, and the kinetics of [3H]inositol efflux and insulin secretion were measured. MMSucc induced a rapid and sustained dose-dependent increase in [3H]inositol efflux rates. In batch-incubated islets, MMSucc increased inositol phosphate levels. Finally, MMSucc (20 mM), in the presence of 8 mM glucose, did not influence the detritiation of [5-3H]glucose, but reduced the oxidation of [U-14C] glucose. These results support the following conclusions. First, MMSucc is a potent activator of islet phosphoinositide hydrolysis. Second, the activation of protein kinase-C appears to contribute to the acute insulin secretory effect of MMSucc. Third, MMSucc-induced increases in phosphoinositide hydrolysis contribute at least in part to its ability to acutely stimulate insulin release and prime the beta-cell to subsequent stimulation. Finally, mitochondrial events associated with the oxidative metabolism of MMSucc may underlie its insulinotropic action.
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PMID:Biochemical mechanisms involved in monomethyl succinate-induced insulin secretion. 132 78

The phosphorylation of diacylglycerol (DG), a reaction catalyzed by DG kinase, may be critical in the termination of effector-induced signals mediated by protein kinase C. Synapsin I is a principal target of intracellular protein kinases and is thought to be involved in the release of neurotransmitter from axon terminals. We present several lines of evidence which indicate that rat brain synapsin, in addition to this role, may function as a DG kinase. Purified rat brain DG kinase was digested with trypsin, which produced three major fragments whose sequence was identical to three regions in synapsin I. Using a rabbit anti-synapsin polyclonal antiserum, the elution profile of synapsin immunoreactivity coincided exactly with that of DG kinase activity in column fractions from the final step in the DG kinase purification procedure. As is the case with synapsin, the purified enzyme was a strongly basic protein with an isoelectric point greater than 10.0. Finally, incubating the DG kinase with highly purified bacterial collagenase, an enzyme that partially degrades the proline- and glycine-rich synapsin, resulted in the simultaneous loss of DG kinase activity and synapsin immunoreactivity. We conclude that cytosolic rat brain synapsin is capable of functioning as a DG kinase.
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PMID:Cytosolic rat brain synapsin I is a diacylglycerol kinase. 164 30

In the last 10 years precise cellular functions of alpha-tocopherol, some of which are independent of its antioxidant/radical-scavenging ability, have been revealed. Absorption of alpha-tocopherol from the gut is a selective process. Other tocopherols are not absorbed or are absorbed to a lesser extent. At the post-translational level, alpha-tocopherol inhibits protein kinase C and 5-lipoxygenase and activates protein phosphatase 2A and diacylglycerol kinase. Some genes [platelet glycoprotein IV/thrombospondin receptor/class B scavenger receptor (CD36), alpha-tocopherol transfer protein (alpha-TTP), alpha-tropomyosin, connective tissue growth factor and collagenase] are affected by alpha-tocopherol at the transcriptional level. alpha-Tocopherol also inhibits cell proliferation, platelet aggregation, monocyte adhesion and the oxygen burst in neutrophils. Other antioxidants, such as beta-tocopherol and probucol, do not mimic these effects, suggesting a nonantioxidant, alpha-tocopherol-specific molecular mechanism.
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PMID:Specific cellular responses to alpha-tocopherol. 1086 30

Recent research on alpha-tocopherol has revealed specific cellular functions of this compound belonging to the vitamin E family. Alpha-tocopherol can act as a radical scavenger, as a pro-oxidant, as an anti-alkylation agent and, most important, by mechanisms that are independent of the above properties. To the last group belong protein kinase C and 5-lipoxygenase inhibition at post-translational level, as well as alpha-tocopherol activation of protein phosphatase 2A and diacylglycerol kinase. Furthermore, at transcriptional level, several genes (CD36, alpha-TTP, alpha-tropomyosin, and collagenase) are modulated by alpha-tocopherol. These effects result in inhibition of smooth muscle cell proliferation, platelet aggregation, and monocyte adhesion and may be related to the alleged protection of atherosclerosis by vitamin E. On the other side, epidemiological and intervention studies have shown some inconsistent results. Rather than disregarding vitamin E as a means to protect against atherosclerosis progression, it would be wiser to better design clinical trials based on current knowledge of the biological properties of the molecule.
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PMID:Vitamin E 80th anniversary: a double life, not only fighting radicals. 1179 98

Molecules provided with an antioxidant function may have additional properties, the latter being sometimes of greater importance than the former. In the last ten years, alpha-tocopherol has revealed precise cellular functions, some of which are independent of its antioxidant/radical scavenging ability. At the posttranslational level, alpha-tocopherol inhibits protein kinase C and 5-lipoxygenase and activates protein phosphatase 2A and diacylglycerol kinase. Some genes (CD36, alpha-TTP, alpha-tropomyosin, and collagenase) are affected by alpha-tocopherol at the transcriptional level. alpha-Tocopherol also induces inhibition of cell proliferation, platelet aggregation and monocyte adhesion. These effects are unrelated to the antioxidant activity of vitamin E, but rather are believed to be a result of specific interactions of vitamin E with components of the cell, e. g. proteins, enzymes and membranes. This review focuses on novel non-antioxidant functions of alpha-tocopherol and discusses the possibility that many of the effects previously attributed to the antioxidant functions can also be explained by non-antioxidant mechanisms.
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PMID:The 80th anniversary of vitamin E: beyond its antioxidant properties. 1203 35

Molecules in biological systems often can perform more than one function. In particular, many molecules have the ability to chemically scavenge free radicals and thus act in the test tube as antioxidant, but their main biological function is by acting as hormones, ligands for transcription factors, modulators of enzymatic activities or as structural components. In fact, oxidation of these molecules may impair their biological function, and cellular defense systems exist which protect these molecules from oxidation. Vitamin E is present in plants in 8 different forms with more or less equal antioxidant potential (alpha-, beta-, gamma-, delta-tocopherol/tocotrienols); nevertheless, in higher organisms only alpha-tocopherol is preferentially retained suggesting a specific mechanism for the uptake for this analogue. In the last 20 years, the route of tocopherol from the diet into the body has been clarified and the proteins involved in the uptake and selective retention of alpha-tocopherol discovered. Precise cellular functions of alpha-tocopherol that are independent of its antioxidant/radical scavenging ability have been characterized in recent years. At the posttranslational level, alpha-tocopherol inhibits protein kinase C, 5-lipoxygenase and phospholipase A2 and activates protein phosphatase 2A and diacylglycerol kinase. Some genes (e. g. scavenger receptors, alpha-TTP, alpha-tropomyosin, matrix metalloproteinase-19 and collagenase) are modulated by alpha-tocopherol at the transcriptional level. alpha-Tocopherol also inhibits cell proliferation, platelet aggregation and monocyte adhesion. These effects are unrelated to the antioxidant activity of vitamin E, and possibly reflect specific interactions of alpha-tocopherol with enzymes, structural proteins, lipids and transcription factors. Recently, several novel tocopherol binding proteins have been cloned, that may mediate the non-antioxidant signaling and cellular functions of vitamin E and its correct intracellular distribution. In the present review, it is suggested that the non-antioxidant activities of tocopherols represent the main biological reason for the selective retention of alpha-tocopherol in the body, or vice versa, for the metabolic conversion and consequent elimination of the other tocopherols.
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PMID:Non-antioxidant activities of vitamin E. 1513 10