page_title: Diguanylate cyclase
section_title: Activation Mechanism and Regulation
hierarchical_section_title: Diguanylate cyclase / Activation Mechanism and Regulation
caption_attribution_description: English: A possible mechanism for c-di-GMP formation utilizing a nucleophilic attack on the alpha-phosphate
context_page_description: In enzymology, diguanylate cyclase, also known as diguanylate kinase, is an enzyme that catalyzes the chemical reaction:
  2 Guanosine triphosphate ↔ 2 diphosphate + cyclic di-3',5'-guanylate
  The substrates of diguanylate cyclases are two molecules of guanosine triphosphate and the products are two molecules of diphosphate and one molecule of cyclic di-3’,5’-guanylate.
  Degradation of cyclic di-GMP to guanosine monophosphate is catalyzed by a phosphodiesterase.
context_section_description: The crystal structure of the C. crescentus diguanylate cyclase, PleD, contains three domains; a GGDEF domain with diguanylate cyclase activity and two CheY-like receiver domains (D1/D2).  As seen in the figure, the active form of PleD is a dimer which forms by phosphorylation of the first receiver domain (D1). Phosphorylation of the receiver domain increases the dimerization affinity by approximately 10-fold over non-phosphorylated domains.
  Inhibition of DGC activity is thought to be allosteric and non-competitive. Cyclic di-GMP binds to interface between the DGC and D2 domains stabilizing the open structure and preventing catalysis.   Strong product inhibition has been observed with a Ki of 0.5 μM.
  Though the exact catalytic mechanism has not been resolved, it is hypothesized that the dimerized structure of PleD facilitates interaction of the two GTP molecules within the DGC active site for cyclization. A proposed mechanism by Chan et al. indicates that the 3'-OH group of the GTP is deprotonated by a glutamic acid residue (E370) to allow for intermolecular nucleophilic attack of the α-phosphate.  The  pentachoordinated transition state created through this nucleophilic attack is possibly stabilized by a Lysine residue (K332).
caption: c-di-GMP formation: In PleD residue E370 may act as a generic base and K332 may stabilize charge on pentachoordinated transition state
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