Adenylation

Adenylylation, now known as AMPylation, is a process in which adenosine monophosphate (AMP) molecule is covalently attached to a protein side chain, altering the function of the protein. This covalent addition of AMP to a hydroxyl side chain of the protein is posttranslational modification that is stable and reversible. Adenylylation involves a phosphodiester bond between a hydroxyl group of the molecule undergoing adenylylation and the phosphate group of the adenosine monophosphate nucleotide (i.e. adenylic acid). This process can occur to molecules such as tyrosine residues. Enzymes that are capable of catalyzing this process are called AMPylators.

Similar to serine, threonine or tyrosine phosphorylation, AMPylation regulates the activity of some proteins, such as glutamine synthetase. Additionally, AMPylation aids in allowing thermodynamically unfavorable overall reactions to take place by generating a leaving group in chemical mechanisms that indirectly use energy from ATP hydrolysis. Unstable carboxylate-phosphate mixed anhydrides or of phosphoramidates are generated in this transient adenylyation reaction

The degree of adenylylation depends on the ratio of glutamine to α-ketoglutarate: The higher this ratio the more monomers are adenylylated, thereby producing lower activity of glutamine synthetase; the lower the ratio the less monomers are adenylated and the higher activity of glutamine synthetase. A high ratio is a sign of cellular nitrogen sufficiency, whereas a low ratio is evidence of a limited nitrogen and the need for ammonia fixation by glutamine synthetase.

AMPylators are enzymes that catalyze AMPylation. These enzymes have been shown to be comparable to kinases due to their ATP hydrolysis activity and reversible transfer of the metabolite to a hydroxyl side chain of the protein substrate. To date, the AMPylators that have been identified are bacterial proteins. Two domains, the Fic and adenylyl transferase domains, are the currently known AMPylators that have been shown to be involved in pathogenicity of bacterial species and metabolic regulation. Fic domains are evolutionarily conserved domains in prokaryotes and eukaryotes that belong to the Fido domain superfamily, whereas the adenylyl transferase domains are part of the larger nucleotidyl transferase protein family

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