Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lithium therapy is the therapeutic mainstay for bipolar disorder and has been associated in the thyroid with euthymic goiter, hyper and hypothyroidism as well as thyroid autoimmune disease. The FRTL-5 cell line is a well known model of thyroid cell physiology, where lithium has been shown to increase 3H-thymidine uptake at concentrations of 2 mM. This mitogenic effect was not associated with adenylate cyclase as measured by cyclic adenosine monophosphate (cAMP) production. The de novo synthesis of cholesterol is an important signal transduction pathway in FRTL-5 cells, where newly synthesized Rho GTPase is geranylgeranylated, enabling membrane localization of the G-protein and subsequent G1 to S-phase transition, resulting from extracellular stimulation. Here we confirm lithium mitogenicity at therapeutically relevant concentrations (1 mM) and demonstrate a lithium-associated accumulation of FRTL-5 cells in S-phase of the cell cycle. These effects could be abolished by Pravastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), the rate-limiting enzyme in the formation of intermediates (de novo cholesterol synthesis) required for G-protein prenylation. Pravastatin, similar to lithium, showed no effect on cAMP production either under basal or thyroid stimulating hormone (TSH)-stimulated conditions indicating that de novo cholesterol synthesis is not involved with adenylate cyclase. The inhibitory effect of pravastatin could be overcome by reinitiating de novo cholesterol synthesis. This was achieved by the addition of the cell permeable, first metabolite (mevalonate) after HMG-CoA, which allowed the cycle to continue, leading eventually to protein prenylation, despite the presence of Pravastatin. These novel findings demonstrate lithium involvement in de novo cholesterol synthesis and G-protein prenylation, an important signal transduction pathway in FRTL-5 cells.
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PMID:Mitogenic effect of lithium in FRTL-5 cells can be reversed by blocking de novo cholesterol synthesis and subsequent signal transduction. 1080 58

cAMP plays a critical role in the control of oocyte maturation, as a high level of cAMP maintains oocyte arrest at the first meiotic prophase. Yet this study shows that pulsing meiotically arrested denuded oocytes (DO) with cAMP induces oocyte maturation through the activation of AMP-activated protein kinase (PRKA). Short-term (3 h) pulsing of meiotically arrested oocytes with forskolin, an adenyl cyclase (AC) activator, increased oocyte cAMP, led to elevated AMP, and induced oocyte meiotic resumption compared to oocytes continuously cultured in the control medium with or without forskolin. Western analysis showed that germinal vesicle (GV)-stage oocytes after forskolin pulsing contained increased levels of phospho-acetyl CoA carboxylase (pACACA), a primary substrate of PRKA. Pulsing oocytes with the phosphodiesterase (PDE)-sensitive cAMP analog, 8-bromo-cAMP (8-Br-cAMP), also increased pACACA and pPRKA levels in GV-stage oocytes and induced oocyte meiotic resumption. Moreover, the PRKA inhibitors, compound C and araA, prevented 8-Br-cAMP pulsing-induced maturation. The lack of effect on meiotic induction and PRKA activation when oocytes were pulsed with the PDE-resistant activators of cAMP-dependent protein kinase, Sp-cAMP-AM and Sp-5,6-DCI-cBIMPS, suggests that cAMP degradation is required for pulsing-induced maturation. Pulsing oocytes with the exchange protein directly activated by cAMP (Epac)-specific activator, 8-CPT-2'-O-Me-cAMP, had no stimulatory effect on oocyte maturation, suggesting Epac is not involved in the pulsing-induced maturation. Taken together, these data support the idea that a transient increase in oocyte cAMP can induce meiotic resumption via activation of PRKA.
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PMID:cAMP pulsing of denuded mouse oocytes increases meiotic resumption via activation of AMP-activated protein kinase. 1970 May 29

Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism. This approach identified two compounds that inhibit the HsaAB enzyme complex, which is required for complete degradation of the cholesterol A/B rings. The strategy also identified an inhibitor of PrpC, the 2-methylcitrate synthase, which is required for assimilation of cholesterol-derived propionyl-CoA into the TCA cycle. These chemical probes represent new classes of inhibitors with novel modes of action, and target metabolic pathways required to support growth of Mtb in its host cell. The screen also revealed a structurally-diverse set of compounds that target additional stage(s) of cholesterol utilization. Mutants resistant to this class of compounds are defective in the bacterial adenylate cyclase Rv1625/Cya. These data implicate cyclic-AMP (cAMP) in regulating cholesterol utilization in Mtb, and are consistent with published reports indicating that propionate metabolism is regulated by cAMP levels. Intriguingly, reversal of the cholesterol-dependent growth inhibition caused by this subset of compounds could be achieved by supplementing the media with acetate, but not with glucose, indicating that Mtb is subject to a unique form of metabolic constraint induced by the presence of cholesterol.
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PMID:Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium's metabolism is constrained by the intracellular environment. 2567 47


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