Adenylyl cyclase

Adenylyl cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylate cyclase, abbreviated AC) is an enzyme with key regulatory roles in essentially all cells. It is the most polyphyletic known enzyme: six distinct classes have been described, all catalyzing the same reaction but representing unrelated gene families with no known sequence or structural homology. The best known class of adenylyl cyclases is class III or AC-III (Roman numerals are used for classes). AC-III occurs widely in eukaryotes and has important roles in many human tissues.Beta adrenergic receptor kinase pathway Adenylyl cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylate cyclase, abbreviated AC) is an enzyme with key regulatory roles in essentially all cells. It is the most polyphyletic known enzyme: six distinct classes have been described, all catalyzing the same reaction but representing unrelated gene families with no known sequence or structural homology. The best known class of adenylyl cyclases is class III or AC-III (Roman numerals are used for classes). AC-III occurs widely in eukaryotes and has important roles in many human tissues. All classes of adenylyl cyclase catalyse the conversion of adenosine triphosphate (ATP) to 3',5'-cyclic AMP (cAMP) and pyrophosphate. Magnesium ions are generally required and appears to be closely involved in the enzymatic mechanism. The cAMP produced by AC then serves as a regulatory signal via specific cAMP-binding proteins, either transcription factors, enzymes (e.g., cAMP-dependent kinases), or ion transporters. The first class of adenylyl cyclases occur in many bacteria including E. coli (as CyaA P00936 ). This was the first class of AC to be characterized. It was observed that E. coli deprived of glucose produce cAMP that serves as an internal signal to activate expression of genes for importing and metabolizing other sugars. cAMP exerts this effect by binding the transcription factor CRP, also known as CAP. Class I AC's are large cytosolic enzymes (~100 kDa) with a large regulatory domain (~50 kDa) that indirectly senses glucose levels. As of 2012, no crystal structure is available for class I AC. Some indirect structural information is available for this class. It is known that the N-terminal half is the catalytic portion, and that it requires two Mg2+ ions. S103, S113, D114, D116 and W118 are the five absolutely essential residues. The class I catalytic domain (Pfam PF12633) belongs to the same superfamily (Pfam CL0260) as the palm domain of DNA polymerase beta (Pfam PF18765). Aligning its sequence onto the structure onto a related archaeal CCA tRNA nucleotidyltransferase (PDB: 1R89​) allows for assignment of the residues to specific functions: γ-phosphate binding, structual stablization, DxD motif for metal ion binding, and finally ribose binding. These adenylyl cyclases are toxins secreted by pathogenic bacteria such as Bacillus anthracis, Bordetella pertussis, Pseudomonas aeruginosa, and Vibrio vulnificus during infections. These bacteria also secrete proteins that enable the AC-II to enter host cells, where the exogenous AC activity undermines normal cellular processes. The genes for Class II ACs are known as cyaA, one of which is anthrax toxin. Several crystal structures are known for AC-II enzymes. These adenylyl cyclases are the most familiar based on extensive study due to their important roles in human health. They are also found in some bacteria, notably Mycobacterium tuberculosis where they appear to have a key role in pathogenesis. Most AC-III's are integral membrane proteins involved in transducing extracellular signals into intracellular responses. A Nobel Prize was awarded to Earl Sutherland in 1971 for discovering the key role of AC-III in human liver, where adrenaline indirectly stimulates AC to mobilize stored energy in the 'fight or flight' response. The effect of adrenaline is via a G protein signaling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell (cytoplasm). The outside signal (in this case, adrenaline) binds to a receptor, which transmits a signal to the G protein, which transmits a signal to adenylyl cyclase, which transmits a signal by converting adenosine triphosphate to cyclic adenosine monophosphate (cAMP). cAMP is known as a second messenger. Cyclic AMP is an important molecule in eukaryotic signal transduction, a so-called second messenger. Adenylyl cyclases are often activated or inhibited by G proteins, which are coupled to membrane receptors and thus can respond to hormonal or other stimuli. Following activation of adenylyl cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels. Photoactivatable adenylyl cyclase (PAC) was discovered in Euglena gracilis and can be expressed in other organisms through genetic manipulation. Shining blue light on a cell containing PAC activates it and abruptly increases the rate of conversion of ATP to cAMP. This is a useful technique for researchers in neuroscience because it allows them to quickly increase the intracellular cAMP levels in particular neurons, and to study the effect of that increase in neural activity on the behavior of the organism. For example, PAC expression in certain neurons has been shown to alter the grooming behavior in fruit flies exposed to blue light. A green-light activated rhodopsin adenylyl cyclase (CaRhAC) has recently been engineered by modifying the nuclecotide binding pocket of rhodopsin guanylyl cyclase from the fungus Catenaria anguillulae. Most class III adenylyl cyclases are transmembrane proteins with 12 transmembrane segments. The protein is organized with 6 transmembrane segments, then the C1 cytoplasmic domain, then another 6 membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site. In Mycobacterium tuberculosis and many other bacterial cases, the AC-III polypeptide is only half as long, comprising one 6-transmembrane domain followed by a cytoplasmic domain, but two of these form a functional homodimer that resembles the mammalian architecture with two active sites. In non-animal class III ACs, the catalytic cytoplasmic domain is seen associated with other (not necessarily transmembrane) domains.