Biology:Soluble adenylyl cyclase

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Short description: Regulatory cytosolic enzyme

Soluble adenylyl cyclase (sAC) is a regulatory cytosolic enzyme present in almost every cell. sAC is a source of cyclic adenosine 3’,5’ monophosphate (cAMP) – a second messenger that mediates cell growth and differentiation in organisms from bacteria to higher eukaryotes. sAC differentiates from the transmembrane adenylyl cyclase (tmACs) – an important source of cAMP; in that sAC is regulated by bicarbonate anions and it is dispersed throughout the cell cytoplasm. sAC has been found to have various functions in physiological systems different from that of the tmACs.[1]

Genomic context and summary

A
Gene Structure: Chromosome: 1; NC_000001.10 (167778625..167883453, complement)

sAC is encoded in a single Homo sapiens gene identified as ADCY10 or Adenylate cyclase 10 (soluble). This gene packed down 33 exons that comprise greater than 100kb; though, it seems to utilize multiple promoters,[2][3] and its mRNA undergoes extensive alternative splicing.[2][3][4][5]

Structure

The functional mammalian sAC consist of two heterologous catalytic domains (C1 and C2), forming the 50 kDa amino terminus of the protein.[6][7] The additional ~140 kDa C terminus of the enzyme includes an autoinhibitory region,[8] canonical P-loop, potential heme-binding domain,[9] and leucine zipper-like sequence,[10] which are a form of putative regulatory domains.

A truncated form of the enzyme only includes the C1 and C2 domains and it is refers to as the minimal functional sAC variant.[5][10] This sAC-truncated form has cAMP-forming activity much higher than its full-length type. These sAC variants are stimulated by HCO3- and respond to all known selective sAC inhibitors.[6] Crystal structures of this sAC variant comprising only the catalytic core, in apo form and in as complex with various substrate analogs, products, and regulators, reveal a generic Class III AC architecture with sAC-specific features.[11] The structurally related domains C1 and C2 form the typical pseudo-heterodimer, with one active site.[6] The pseudo-symmetric site accommodates the sAC-specific activator HCO3−, which activates by triggering a rearrangement of Arg176, a residue connecting both sites. The anionic sAC inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) acts as a blocker for the entrance to active site and bicarbonate binding pocket.[11]

Activation by bicarbonate (HCO−3) and calcium (Ca2+)

The binding and cyclizing of adenosine 5’ triphosphate (ATP) to the catalytic active site of the enzyme is coordinated by two metal cations. The catalytic activity of sAC is increase by the presence of manganese [Mn2+]. sAC magnesium [Mg2+] activity is regulated by calcium [Ca2+] which increases the affinity for ATP of mammalian sAC. In addition, bicarbonate [HCO−3] releases ATP-Mg2+ substrate inhibition and increases Vmax of the enzyme.[12]

The open conformation state of sAC is reached when ATP, with Ca2+ bound to its γ-phosphate binds with specific residues in the catalytic center of the enzyme. When the second metal – a Mg2+ ion – binds to the α-phosphate of ATP leads to a conformational change of the enzyme: the close state. The change in conformation from open to close state induces esterification of the α-phosphate with the ribose in adenosine and the release of the β- and γ-phosphates, this leads to cyclizing.[7] Hydrogencarbonate stimulates the enzyme’s Vmax by promoting the allosteric change that leads to active site closure, recruitment of the catalytic Mg2+ ion, and readjustment of the phosphates in the bound ATP.[13] The activator bicarbonate binds to a site pseudo-symmetric to the active site and triggers conformational changes by recruiting Arg176 from the active site (see above - "structure").[11] Calcium increases substrate affinity by replacing the magnesium in the ion B site, which provides an anchoring point for the beta- and gamma-phosphates of the ATP substrate.[11][13]

Sources of bicarbonate (HCO−3)and calcium (Ca2+)

  • bicarbonate derived from carbonic anhydrase (CA)-dependent hydration.
  • CO2 metabolism
  • Enters through membrane-transporting proteins or cystic fibrosis transmembrane conductance regulators.
  • Calcium enters by voltage-dependent Ca2+ channels or by release from the endoplasmic reticulum.
  • Hydrogencarbonate and calcium activates sAC in the nucleus.
  • sAC inside mitochondria is activated by metabolically generated CO2 through carbonic anhydrase.

Physiological effects

Brain and nervous system

Astrocytes express several sAC splice variants,[14] which are involved in metabolic coupling between neurons and astrocytes. Increase of potassium [K+] in the extracellular space caused by neuronal activity depolarizes the cell membrane of nearby astrocytes and facilitates the entry of hydrogencarbonate through Na+/HCO−3- cotransporters.[7] The increase in cytosolic hydrogencarbonate activates sAC; the result of this activation is the release of lactate for use as energy source by the neurons.

Bone

Numerous sAC splice variants are present in osteoclast and osteoblasts,[3] and mutation in the human sAC gene is associated with low spinal density.[15] Calcification by osteoblasts is intrinsically related with bicarbonate and calcium. Bone density experiments in mouse calvaria [16] cultured indicates that HCO−3-sensing sAC is a physiological appropriate regulator of bone formation and/or reabsorption.

Sperm

sAC activation by bicarbonate is necessary for motility and other aspects of capacitation in the spermatozoa of mammals.[17][18] In human males, mutations in the ADCY10 gene that lead to the inactivation of sAC have been linked to cases of sterility.[19] Due to this essential role in male fertility, sAC has been explored as a potential target for non-hormonal male contraception. [20]

References

  1. ↑ "Bicarbonate, carbon dioxide and pH sensing via mammalian bicarbonate-regulated soluble adenylyl cyclase". Interface Focus 11 (2): 20200034. April 2021. doi:10.1098/rsfs.2020.0034. PMID 33633833. 
  2. ↑ 2.0 2.1 "Somatic 'soluble' adenylyl cyclase isoforms are unaffected in Sacy tm1Lex/Sacy tm1Lex 'knockout' mice". PLOS ONE 3 (9): e3251. September 2008. doi:10.1371/journal.pone.0003251. PMID 18806876. Bibcode: 2008PLoSO...3.3251F. 
  3. ↑ 3.0 3.1 3.2 "Cloning and characterization of the human soluble adenylyl cyclase". American Journal of Physiology. Cell Physiology 288 (6): C1305–C1316. June 2005. doi:10.1152/ajpcell.00584.2004. PMID 15659711. 
  4. ↑ "Soluble adenylyl cyclase is localized to cilia and contributes to ciliary beat frequency regulation via production of cAMP". The Journal of General Physiology 130 (1): 99–109. July 2007. doi:10.1085/jgp.200709784. PMID 17591988. 
  5. ↑ 5.0 5.1 "Identification and functional analysis of splice variants of the germ cell soluble adenylyl cyclase". The Journal of Biological Chemistry 276 (34): 31698–31708. August 2001. doi:10.1074/jbc.m011698200. PMID 11423534. 
  6. ↑ 6.0 6.1 6.2 "Structure, mechanism, and regulation of soluble adenylyl cyclases - similarities and differences to transmembrane adenylyl cyclases". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1842 (12 Pt B): 2535–2547. December 2014. doi:10.1016/j.bbadis.2014.08.012. PMID 25193033. 
  7. ↑ 7.0 7.1 7.2 "Intracellular cAMP signaling by soluble adenylyl cyclase". Kidney International 79 (12): 1277–1288. June 2011. doi:10.1038/ki.2011.95. PMID 21490586. 
  8. ↑ "Autoinhibitory regulation of soluble adenylyl cyclase". Molecular Reproduction and Development 73 (3): 361–368. March 2006. doi:10.1002/mrd.20409. PMID 16250004. 
  9. ↑ "Identification of a haem domain in human soluble adenylate cyclase". Bioscience Reports 32 (5): 491–499. October 2012. doi:10.1042/BSR20120051. PMID 22775536. 
  10. ↑ 10.0 10.1 "Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals". Proceedings of the National Academy of Sciences of the United States of America 96 (1): 79–84. January 1999. doi:10.1073/pnas.96.1.79. PMID 9874775. Bibcode: 1999PNAS...96...79B. 
  11. ↑ 11.0 11.1 11.2 11.3 "Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate". Proceedings of the National Academy of Sciences of the United States of America 111 (10): 3727–3732. March 2014. doi:10.1073/pnas.1322778111. PMID 24567411. Bibcode: 2014PNAS..111.3727K. 
  12. ↑ "Kinetic properties of "soluble" adenylyl cyclase. Synergism between calcium and bicarbonate". The Journal of Biological Chemistry 278 (18): 15922–15926. May 2003. doi:10.1074/jbc.m212475200. PMID 12609998. 
  13. ↑ 13.0 13.1 "Bicarbonate activation of adenylyl cyclase via promotion of catalytic active site closure and metal recruitment". Nature Structural & Molecular Biology 12 (1): 32–37. January 2005. doi:10.1038/nsmb880. PMID 15619637. 
  14. ↑ "Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase". Neuron 75 (6): 1094–1104. September 2012. doi:10.1016/j.neuron.2012.08.032. PMID 22998876. 
  15. ↑ "Identification and characterization of a gene with base substitutions associated with the absorptive hypercalciuria phenotype and low spinal bone density". The Journal of Clinical Endocrinology and Metabolism 87 (4): 1476–1485. April 2002. doi:10.1210/jcem.87.4.8300. PMID 11932268. 
  16. ↑ "Inhibition of osteoclast formation and function by bicarbonate: role of soluble adenylyl cyclase". Journal of Cellular Physiology 220 (2): 332–340. August 2009. doi:10.1002/jcp.21767. PMID 19360717. 
  17. ↑ "Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization". Developmental Biology 296 (2): 353–362. August 2006. doi:10.1016/j.ydbio.2006.05.038. PMID 16842770. 
  18. ↑ "Bicarbonate actions on flagellar and Ca2+ -channel responses: initial events in sperm activation". Development 130 (7): 1317–1326. April 2003. doi:10.1242/dev.00353. PMID 12588848. 
  19. ↑ Akbari, Arvand; Pipitone, Giovanni Battista; Anvar, Zahra; Jaafarinia, Mojtaba; Ferrari, Maurizio; Carrera, Paola; Totonchi, Mehdi (4 June 2019). "ADCY10 frameshift variant leading to severe recessive asthenozoospermia and segregating with absorptive hypercalciuria". Human Reproduction 34 (6): 1155–1164. doi:10.1093/humrep/dez048. PMID 31119281. 
  20. ↑ Balbach, Melanie; Rossetti, Thomas; Ferreira, Jacob; Ghanem, Lubna; Ritagliati, Carla; Myers, Robert W.; Huggins, David J.; Steegborn, Clemens et al. (14 February 2023). "On-demand male contraception via acute inhibition of soluble adenylyl cyclase". Nature Communications 14 (1): 637. doi:10.1038/s41467-023-36119-6. PMID 36788210. Bibcode: 2023NatCo..14..637B. 

Further reading



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