Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase is shown to occur in ram semen, and its activity to be higher in spermatozoa than in seminal plasma. Using similar substrate levels, the rate at which adenosine 3',5'-monophosphate (cyclic AMP) is metabolized by phosphodiesterase in spermatozoa is about 100 times higher than that of cyclic AMP synthesis by adenylate cyclase. In spermatozoa, phosphodiesterase is present partly in a soluble form, and partly bound; both forms can be extracted by sonication. The soluble enzyme (pH optimum 8-0, Km = 1-5 muM, mol. wt 165,000) occurs as a single isoenzyme, as shown by polyacrylamide gel electrophoresis and anion-exchange chromatography; this isoenzyme appears to be specific for spermatozoa and its formation in the testis coincides with the appearance of spermatozoa. The bound sperm enzyme has been solubilized with Trion X-100; it is a single isoenzyme (pH optimum 8-0, mol. wt 165,000) which is electrophoretically different from the soluble form, but similar to the phosphodiesterase found in other tissues. Seminal plasma phosphodiesterase (pH optimum 8-8, mol. wt 165,000) is present in the form of three isoenzymes; all three are different from the two forms of sperm phosphodiesterase, but are similar to the isoenzymes found in certain male accessory organs.
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PMID:Investigations on adenosine 3',5'-monophosphate phosphodiesterase in ram semen and initial characterization of a sperm-specific isoenzyme. 17 69

Luteinizing hormone (LH) levels were measured in the seminal plasma of 68 fertile and infertile men. LH levels in the seminal plasma were severalfold higher than those normally found in serum and were significantly higher in oligospermic and normospermic samples than in azoospermic samples. However, no significant difference was observed in LH levels of oligospermic and normospermic men. The effects of LH on fructose utilization, glucose oxidation, and adenyl cyclase activity of spermatozoa were also examined. The results indicate a possible role of seminal plasma LH in sperm motility and metabolism.
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PMID:Levels of luteinizing hormone in semen of fertile and infertile men and possible significance of luteinizing hormone in sperm metabolism. 95 35

The effect of prolactin on adenyl cyclase, rate of fructose utilization, and glucose oxidation by human spermatozoa was studied. Prolactin stimulated all of these processes at a concentration generally available in seminal plasma. These results suggest that prolactin plays an important role in the energy metabolism of human spermatozoa.
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PMID:Effect of prolactin on metabolism of human spermatozoa. 97 1

A distinctive Mn-2+-sensitive adenylate cyclase [ATP pyrophosphate-lyase(cyclizing), EC 4.6.1.1] system insensitive to fluoride has been found in rat seminiferous tubules and epididymal sperm. The development of this distinctive adenylate cyclase in testis was studied during spermatogenesis. It was first detectable in seminiferous tubules in immature rats at about the time of the first reductive divisions and the appearance of spermatid cells. The specific activity of the enzyme increased substantially during the period of spermatogenesis when spermatids develop into mature spermatozoa, and reached maximal values in the testis of adult rats. After centrifugation of testis tissue homogenates at 105,000 X g for 60 min, the Mn-2+-sensitive adenylate cyclase activity was found in the cytosol. The enzyme remains in solution after centrifugation at 300,000 X g for 5 hr or at 180,000 X g for 24 hr and passes through a 0.22 mum Millipore filter. Electron microscopic examination showed no visible membrane fragments or vesicles in the filtered supernatant. The Mn-2+-sensitive adenylate cyclase system is also present in epidiymal sperm. However, in the sperm obtained from either the caput or the cauda of epididymis, the adenylate cyclase is membrane-associated and found in particulate fractions of sperm homogenates. It therefore appears that the Mn-2+-sensitive adenylate cyclase is initially present in the cytoplasm either unattached or loosely bound to intracellular membranes and becomes firmly attached to sperm membranes later in development. This occurs either during the process of maturation of spermatids into sperm or during the transport of the testicular sperm into the epididymis.
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PMID:Development of a Mn-2+-sensitive, "soluble" adenylate cyclase in rat testis. 105 68

The acrosome reaction of spermatozoa appears to be analogous to various somatic cell exocytotic events which involve cascade reactions, i.e., transmission of an external signal across the cell membrane resulting in activation of an "amplifier" enzyme and the generation of a second messenger. Using a synchronous acrosome reaction system (De Jonge et al., J. Androl., 10:232-239, '89a), it was found that analogues of the second-messenger cAMP, dibutyryl cAMP (dbcAMP) and 8-bromo cAMP, stimulated the acrosome reaction of capacitated spermatozoa. Additionally, treatment of spermatozoa with either xanthine or non-xanthine phosphodiesterase inhibitors induced a significant (P less than 0.05) increase in the percent acrosome reaction after a period of capacitation in comparison to untreated controls. These results indicate that analogues of cAMP or inhibitors which prevent cAMP hydrolysis can induce the human sperm acrosome reaction. Subsequent experiments were conducted to test whether the amplifier enzyme in the cascade reaction, adenylate cyclase, has a role in the acrosome reaction. Forskolin, an adenylate cyclase stimulator, caused a significant (P less than 0.01) increase in the percent acrosome reaction in comparison to controls. Modulators of adenylate cyclase--adenosine, 2'-0-methyladenosine, and 2',3'-dideoxyadenosine--significantly (P less than 0.01) inhibited the forskolin-induced acrosome reaction. dbcAMP was able to overcome the inhibition by adenosine. Two inhibitors of protein kinase A, the Walsh inhibitor and H-8, caused a significant (P less than 0.01) inhibition of the dbcAMP-induced acrosome reaction. Finally, in the absence of extracellular calcium, dbcAMP induced a significant (P less than 0.01) increase in the acrosome reaction in contrast to A23187. These results suggest that: 1) a molecular mechanism for the human sperm acrosome reaction involves the cAMP second-messenger system; i.e., activation of adenylate cyclase, the amplifier enzyme that produces cAMP, production of cAMP as a second messenger, and activation of cAMP-dependent kinase A; and that 2) activation of adenylate cyclase occurs after calcium influx.
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PMID:Modulation of the human sperm acrosome reaction by effectors of the adenylate cyclase/cyclic AMP second-messenger pathway. 165 65

Previous studies from this laboratory and others have identified several enzymes on the surface of mammalian spermatozoa. Some of these enzymes, namely a galactosyltransferase and a novel alpha-D-mannosidase, are believed to play a ligand-like role in recognizing and binding to the complementary moiety(ies) present on zona pellucida glycoconjugates. However, little or no information is available about the occurrence of these enzymes in human spermatozoa. In the present report, we show that a very small amount of the total galactosyltransferase activity present in human semen is associated with spermatozoa. Moreover, our failure to find a significant amount of the enzyme on sperm plasma membranes suggests that the enzyme is not associated with the sperm surface. Therefore, it is unlikely that galactosyltransferase in humans has the same ligand-like role in zona binding that is demonstrated in mouse sperm. In contrast, nearly 5% of alpha-D-mannosidase activity was repeatedly found in the salt-washed plasma membrane fraction. The recovery and enrichment of the alpha-D-mannosidase was nearly one-half that observed for adenylate cyclase and nearly one-third that for phosphodiesterase I, the two sperm plasma membrane marker enzymes. The differential enrichment and recovery of the sperm surface alpha-D-mannosidase is consistant with our previous studies in rat spermatozoa, and suggests that alpha-D-mannosidase may be localized on morphologically distinct region(s) of the sperm plasma membranes. The properties of human sperm surface alpha-D-mannosidase are quite similar to those reported by us for rat sperm plasma membrane mannosidase, but quite different from human sperm acid alpha-D-mannosidase. In addition, whereas anti-rat epididymal alpha-D-mannosidase antibody (IgG-fraction) cross-reacted with the human sperm acid alpha-D-mannosidase, no cross-reactivity was observed with the sperm surface mannosidase. A small amount of fucosyltransferase (less than 1% of the enzyme originally present on spermatozoa) was found in the salt-washed plasma membrane, but the enrichment of the enzyme was only one-tenth of that observed for adenylate cyclase. The potential ligand-like role of human sperm surface alpha-D-mannosidase and other sperm surface enzymes during fertilization is discussed.
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PMID:Human sperm plasma membranes possess alpha-D-mannosidase activity but no galactosyltransferase activity. 211 23

Calmodulin (CaM) affinity chromatography of a detergent extract of sea urchin sperm yielded approximately 20 major proteins. One of these proteins, of Mr 190,000, was purified and used to immunize rabbits. After absorption with living sperm, the serum reacted monospecifically on one- and two-dimensional Western immunoblots with the Mr 190,000 protein. The anti-190-kD serum inhibited 94% of the adenylate cyclase (AC) activity of the CaM eluate. An immunoaffinity column removed 95% of the AC activity, and the purified (but inactive) Mr 190,000 protein was eluted from the column. The antiserum also inhibited 23% of the activity of bovine brain CaM-sensitive AC and 90% of the activity of horse sperm CaM-sensitive AC. These data support the hypothesis that the Mr 190,000 protein is sea urchin sperm AC. Although this AC bound to CaM, it was not possible to demonstrate directly a Ca2+ or CaM sensitivity. However, two CaM antagonists, calmidazolium and chlorpromazine, both inhibited AC activity, and the inhibition was released by added CaM, suggesting the possibility of regulation of this AC by CaM. Indirect immunofluorescence showed the Mr 190,000 protein to be highly concentrated on only the proximal half of the sea urchin sperm flagellum. This asymmetric localization of AC may be important to its function in flagellar motility. This is the first report of the identification of an AC from animal spermatozoa.
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PMID:Identification of sea urchin sperm adenylate cyclase. 212 42

Phorbol esters stimulate cyclic adenosine 3',5'-monophosphate (cAMP) accumulation in hamster spermatozoa under conditions for in vitro capacitation. The 20-50-fold elevation of cAMP levels induced by 1 microM phorbol 12-myristate 13-acetate (PMA) in spermatozoa depends on the presence of sodium bicarbonate in the medium (ED50: 15 mM) and it is independent of extracellular pH. Sodium bicarbonate stimulates adenylate cyclase activity in membrane preparations by 4-fold (ED50: 40 mM). After solubilization, the bicarbonate-sensitive moiety elutes as a single peak of 55 kDa in a gel filtration column. Blockers of bicarbonate chloride antiporters diisothiocyanate stilbene 2,2'-disulfonic acid (DIDS) or acetamido 4'-isothiocyanate stilbene 2,2'-disulfonic acid (SITS) inhibit the bicarbonate dependent PMA effect on cAMP in living spermatozoa (ED50: 100 microM). Maximal (85%) inhibition in cAMP accumulation is observed at 1 mM. Motility is inhibited only at high concentrations of the blockers. Pretreatment of living cells with 1 mM DIDS does not affect membrane adenylate cyclase activity which remains responsive to bicarbonate. These results suggest that controlled transport of bicarbonate through the sperm plasma membrane could be associated to the regulation of cAMP synthesis.
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PMID:Bicarbonate dependence of cAMP accumulation induced by phorbol esters in hamster spermatozoa. 216 11

Earlier studies have provided indirect evidence that the availability of endogenous adenosine can modulate the fertilizing ability of mouse spermatozoa during capacitation. More direct evidence has been sought by evaluating the effect of exogenous adenosine present during the early stages of capacitation. A concentration-dependent stimulation of in-vitro fertilizing ability was observed, with 10 microM- and 100 microM-adenosine significantly increasing the proportion of eggs fertilized compared with drug-free controls. The adenosine-induced stimulation was observed in the presence of 0.01 microM- and 0.1 microM-dipyridamole, an inhibitor of adenosine uptake, suggesting that adenosine is acting at an external site. Comparison of adenosine with its analogues 2'-deoxyadenosine and 2-chloroadenosine indicated that the analogues at 10 microM were able to stimulate fertilization in a manner similar to adenosine. While neither adenosine nor 2'-deoxyadenosine was consistently effective at 1 microM, 2-chloroadenosine significantly stimulated fertilization at both 1 microM and 0.1 microM. In addition, 5'-N-ethylcarboxamidoadenosine (NECA) and (R)-N6-phenylisopropyladenosine (R-PIA), potent analogues in somatic cell systems, proved to be so with mouse sperm suspensions, NECA being stimulatory at greater than or equal to 0.01 microM and R-PIA at greater than or equal to 0.1 microM. Subjective evaluation of motility patterns indicated that more cells exhibited hyperactivated motility in the presence of stimulatory concentrations of adenosine or analogues. Assessment of capacitation state using chlortetracycline fluorescence patterns indicated that incubation in 2'-deoxyadenosine resulted in significantly fewer cells expressing the uncapacitated F pattern and significantly more cells with the capacitated AR (acrosome-reacted) pattern, compared with drug-free counterparts. It is concluded that adenosine promotes capacitation by interacting with externally-directed receptors, possibly on adenylate cyclase to increase the intracellular availability of cyclic adenosine monophosphate (cAMP); cAMP is known to stimulate mouse sperm fertilizing ability. The greater sensitivity to NECA, 2-chloroadenosine and R-PIA, relative to adenosine and 2'-deoxyadenosine, is consistent with interaction at stimulatory A2 adenosine receptors.
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PMID:Adenosine and its analogues, possibly acting at A2 receptors, stimulate mouse sperm fertilizing ability during early stages of capacitation. 240 75

Abalone spermatozoa contain a particulate adenylate cyclase that displays maximal catalytic activity when Mn2+ is present as a metal cofactor in excess of ATP. Unlike other sperm adenylate cyclases, the abalone enzyme displays a high Mg2+-supported catalytic activity (Mg2+/Mn2+ activity ratio = 0.8). Kinetics analyses demonstrate that the enzyme contains both a MgATP catalytic site and a separate Mg2+ regulatory site. Mg2+-supported enzyme activity, however, is not stimulated by guanine nucleotides, NaF, cholera toxin, forskolin, or a variety of hormones. The enzyme from unfractionated sperm homogenates is inhibited by added Ca2+ in a concentration-dependent manner, when EGTA is not present in the assay. Methylxanthines, such as 1-methyl-3-isobutylxanthine and theophylline, also inhibit enzyme activity in a concentration-dependent manner through a noncompetitive mechanism. On the other hand, when intact cells are preincubated with Ca2+ prior to breakage and assayed for enzyme activity, Ca2+ stimulates enzyme activity at low concentrations. Enzyme activity of intact sperm preincubated with methylxanthines, in either the absence or presence of added Ca2+, is also stimulated. This effect is expressed via an effect on the velocity of the enzyme. A-23187 has similar stimulatory effects on the enzyme under these conditions. These data provide further support for the role of Ca2+ conductance in modulating sperm adenylate cyclase activity. The abalone sperm enzyme also appears to have regulatory properties that are unique among other sperm types.
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PMID:Characterization of a calcium-modulated adenylate cyclase from abalone spermatozoa. 241 62


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