Cyclic GMP-AMP synthase
Class of enzyme
From Wikipedia, the free encyclopedia
Cyclic GMP-AMP synthase (cGAS, cGAMP synthase), belonging to the nucleotidyltransferase family, is part of the cytosolic DNA sensor that activates a type-I interferon response (the cGAS-STING DNA sensing pathway). It binds to microbial DNA as well as self DNA that invades the cytoplasm, and catalyzes cGAMP synthesis.[1] In humans, this enzyme is encoded by the gene CGAS, while in some insects this activity has been found in the proteins encoded by genes cGLR1 or cGLR2.[2]
Function
The enzyme catalyses a chemical reaction that produces a specific isomer of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) from the components guanosine triphosphate (GTP) and adenosine triphosphate (ATP), with two units of pyrophosphate (PPi) as a byproduct:
The cyclic product has a bond between the 2'-OH of GMP and the 5'-phosphate of AMP and another between the 3'-OH of AMP and 5'-phosphate of GMP.[3] This cGAMP is a second messenger that binds to and activates the endoplasmic reticulum protein STING to trigger type-I IFNs production.[4][5][3] Mice lacking cGAS are more vulnerable to lethal infection by DNA viruses and RNA viruses.[6][7] In addition, cGAS has been shown to be an innate immune sensor of retroviruses including HIV.[8][9] The human gene encoding cGAS is MB21D1 on chromosome 6.
Human cGAS has been shown to produce less 2'3' cGAMP than mouse cGAS [1][10]. This difference can be explained by the structural differences between mcGAS and hcGAS. Human cGAS is activated in a strongly DNA length-dependent manner [11]. Indeed, human cGAS exhibits a higher affinity for DNA fragments of over 45 bp, whereas mouse cGAS is preferentially activated by shorter DNA sequences. Two amino acids, K187 and L195 in the N-terminus of hcGAS, have been shown to be responsible for human-specific control of 2'3' cGAMP synthesis [10]. The opposing responses of hcGAS and mcGAS to short DNA are completely reversed by the human-specific K187/L195 substitution [10].