Soluble adenylyl cyclase

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.

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, and its mRNA undergoes extensive alternative splicing.

The functional mammalian sAC consist of two heterologous catalytic domains (C1 and C2), forming the 50 kDa amino terminus of the protein. The additional ~140 kDa C terminus of the enzyme includes an autoinhibitory region, canonical P-loop, potential heme-binding domain, and leucine zipper-like sequence, 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. 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. 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. The structurally related domains C1 and C2 form the typical pseudo-heterodimer, with one active site. 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.

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 V_max of the enzyme.

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