Type 10 Soluble Adenylyl Cyclase Is Overexpressed in Prostate Carcinoma and Controls Proliferation of Prostate Cancer Cells

Flacke, Jan-Paul; Flacke, Hanna; Appukuttan, Avinash; Palisaar, Rein-Jüri; Noldus, Joachim; Robinson, Brian D.; Reusch, H. Peter; Zippin, Jonathan H.; Ladilov, Yury

doi:10.1074/jbc.m112.403279

Cited by 48 publications

(47 citation statements)

References 40 publications

(50 reference statements)

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“…Pharmacological sAC modulation has potential therapeutic applications (19)(20)(21)39), and because artificially manipulating the natural activator bicarbonate is problematic in physiological systems, sAC-selective modulators would facilitate in vivo studies. In tmAC, the space corresponding to the hydrophilic sAC BBS between Arg176 (Asn in tmAC) and Lys95 is blocked by a hydrophobic residue (Leu438 in tmACV-C 1 , interacting with Phe338).…”

Section: Resultsmentioning

confidence: 99%

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Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

215

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cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3−); it thereby serves as a cellular sensor for HCO3−, carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3− binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3− activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3− sensing and a basis for targeting this system with drugs.

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Section: Resultsmentioning

confidence: 99%

“…In mammals, sAC acts as a CO 2 /HCO 3 − /pH sensor in processes such as sperm activation (15), acid-base homeostasis (16), and various metabolic responses (10,17,18). sAC has also been implicated in skin and prostate cancer and as a target for male contraceptives (19)(20)(21).…”

mentioning

confidence: 99%

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

215

View full text Add to dashboard Cite

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“…Moreover, nuclear sAC has been suggested to determine the aggressiveness of certain skin and prostate cancers (Flacke et al, 2013;Magro et al, 2012a;Magro et al, 2012b;Zippin et al, 2010). In the heart, sAC controls mitochondria-dependent apoptosis in both coronary endothelial cells (Kumar et al, 2009) and cardiomyocytes (Appukuttan et al, 2012) (reviewed in Chen et al, 2012b).…”

Section: Reviewmentioning

confidence: 99%

Established and potential physiological roles of bicarbonate-sensing soluble adenylyl cyclase (sAC) in aquatic animals

Tresguerres

Barott

Barron

et al. 2014

Journal of Experimental Biology

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Soluble adenylyl cyclase (sAC) is a recently recognized source of the signaling molecule cyclic AMP (cAMP) that is genetically and biochemically distinct from the classic G-protein-regulated transmembrane adenylyl cyclases (tmACs). Mammalian sAC is distributed throughout the cytoplasm and it may be present in the nucleus and inside mitochondria. sAC activity is directly stimulated by HCO 3 -, and sAC has been confirmed to be a HCO 3 -sensor in a variety of mammalian cell types. In addition, sAC can functionally associate with carbonic anhydrases to act as a de facto sensor of pH and CO 2 . The two catalytic domains of sAC are related to HCO 3 --regulated adenylyl cyclases from cyanobacteria, suggesting the cAMP pathway is an evolutionarily conserved mechanism for sensing CO 2 levels and/or acid/base conditions. Reports of sAC in aquatic animals are still limited but are rapidly accumulating. In shark gills, sAC senses blood alkalosis and triggers compensatory H + absorption. In the intestine of bony fishes, sAC modulates NaCl and water absorption. And in sea urchin sperm, sAC may participate in the initiation of flagellar movement and in the acrosome reaction. Bioinformatics and RT-PCR results reveal that sAC orthologs are present in most animal phyla. This review summarizes the current knowledge on the physiological roles of sAC in aquatic animals and suggests additional functions in which sAC may be involved.KEY WORDS: V-ATPase, Acid/base, cAMP, Carbonic anhydrase, pH sensing, Proton pump IntroductionCyclic adenosine monophosphate (cAMP) is the signaling molecule of one of the most versatile and evolutionarily conserved signaling pathways. cAMP is produced by adenylyl cyclase enzymes that use ATP as substrate. There are six different classes of adenylyl cyclases distributed throughout Bacteria, Archaea and Eukarya; these classes are unrelated in sequence and structure but all produce cAMP as a result of convergent evolution (Linder and Schultz, 2008). All known eukaryotic adenylyl cyclases, including soluble adenylyl cyclase (sAC) and transmembrane adenylyl cyclase (tmAC) from animals, belong to Class III. Discovery of mammalian sACUntil recently, vertebrate animals were believed to have only one type of adenylyl cyclase, a family of hormone and G-proteinregulated tmACs. Mammals have nine tmAC genes (ADCY1-9), which differ in their tissue and developmental expression as well as in some of their regulatory properties (Cooper, 2003;Hanoune and Defer, 2001 (Braun, 1974;Braun, 1975;Braun, 1990;Braun, 1991;Braun and Dods, 1975). This enzyme was termed 'soluble adenylyl cyclase' (sAC) because its activity is preferentially found in the cytosolic fraction, although some activity is also found associated with membranes. Subsequent immunolocalization and biochemical studies found sAC in the cell cytoplasm and in organelles (Zippin et al., 2003;Zippin et al., 2004). The intracellular localization of sAC changed the assumption that cAMP is produced exclusively in the proximity of the cell membrane by tmACs. Pr...

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“…Previous studies have demonstrated that KH7 effectively inhibits sAC enzyme activity at concentrations of 10 to 30 μmol/L, whereas transmembrane adenylyl cyclases and soluble guanylyl cyclases remained unaffected. 39 The small molecule KH7 has been identified originally to display an IC 50 between 3 and 10 μmol/L toward the recombinant human ≈55 kDa sAC isoform. 40 Until today, the exact molecular mechanisms underlying the inhibitory effects of KH7 are unknown.…”

Section: Nuclear Sac As a Regulator Of Active Cre Promotersmentioning

confidence: 99%

Soluble Adenylyl Cyclase in Vascular Endothelium

et al. 2014

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Type 10 Soluble Adenylyl Cyclase Is Overexpressed in Prostate Carcinoma and Controls Proliferation of Prostate Cancer Cells

Cited by 48 publications

References 40 publications

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Established and potential physiological roles of bicarbonate-sensing soluble adenylyl cyclase (sAC) in aquatic animals

Soluble Adenylyl Cyclase in Vascular Endothelium

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