Structural Biochemistry/Enzyme Regulation/Adenylation

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Adenylylation of small GTPases by Fic domains and the structures of adenylylated GTPases

Adenylation is the covalent attachment for AMP to a protein side chain. It is known two serve two functions: one as a stable post-translational modification and the other is to generate an efficient leaving group in mechanisms that use energy from the free energy of hydrolysis of phosphoanhydride bond of ATP to allow thermodynamically unfavorable overall reactions to occur.

The activity of glutamine synthetase, an enzyme that plays a key role in the metabolism of nitrogen, is regulated by adenylation. The rate of adenylation depends on the ratio of glutamine to α-ketoglutarate. A low ratio is a sign of cellular nitrogen sufficiency, whereas a high ratio is evidence of a limited nitrogen supply and the need for ammonia fixation by glutamine synthetase.

Adenylation of glutamine synthetase, which is catalyzed by the enzyme adenylyl transferase, involves the phosphodiester bond between the hydroxyl group of the tyrosine residue in glutamine synthetase and the phosphate group of an AMP nucleotide. A complex of adenylyl transferase and a regulatory protein known as PII, which may exist unmodified as PII (also known as PA) and uridylylated as PII-UMP (also known as PD), causes an AMP molecule to either attach to or be removed from the glutamine synthetase, respectively.

A complex of PII with adenylyl transferase catalyzes the attachment of an AMP molecule to glutamine synthetase, forming an adenylated glutamine synthetase that is inactive. On the other hand, a complex of PII-UMP and adenylyl transferase activates deadenylation and removes the AMP from glutamine synthetase, creating deadenylated glutamine synthetase that is active. When there is a higher glutamine to α-ketoglutarate ratio, more monomers of glutamine synthetase are adenylated, thereby producing lower activity. A lower ratio leads to less monomers being adenylated and higher activity of glutamine synthetase.

Adenylation is an important form of regulation for amplifying signals such as for blood clotting and control of glycogen metabolism. Because adenylation is an enzymatic cascade, it is easier for allosteric control, as each enzyme can be a target for regulation. This is important for nitrogen metabolism in cells as it creates many regulatory sites, allowing a cell to fine tune its nitrogen production.


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