PMID:27974467

Citation	Han, X, Shen, L, Wang, Q, Cen, X, Wang, J, Wu, M, Li, P, Zhao, W, Zhang, Y and Zhao, G (2017) Cyclic AMP Inhibits the Activity and Promotes the Acetylation of Acetyl-CoA Synthetase through Competitive Binding to the ATP/AMP Pocket. J. Biol. Chem. 292:1374-1384
Abstract	The high-affinity biosynthetic pathway for converting acetate to acetyl-coenzyme A (acetyl-CoA) is catalyzed by the central metabolic enzyme acetyl-coenzyme A synthetase (Acs), which is finely regulated both at the transcriptional level via cyclic AMP (cAMP)-driven trans-activation and at the post-translational level via acetylation inhibition. In this study, we discovered that cAMP directly binds to Salmonella enterica Acs (SeAcs) and inhibits its activity in a substrate-competitive manner. In addition, cAMP binding increases SeAcs acetylation by simultaneously promoting Pat-dependent acetylation and inhibiting CobB-dependent deacetylation, resulting in enhanced SeAcs inhibition. A crystal structure study and site-directed mutagenesis analyses confirmed that cAMP binds to the ATP/AMP pocket of SeAcs, and restrains SeAcs in an open conformation. The cAMP contact residues are well conserved from prokaryotes to eukaryotes, suggesting a general regulatory mechanism of cAMP on Acs.
Links	PubMed Online version:10.1074/jbc.M116.753640
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
SALTY:NPD		GO:0051591: response to cAMP	ECO:0000314:		P		Organism: Salmonella enterica (Salmonella typhimurium). Paper's Protein Name: NAD+-dependent deacetylase (CobB). UniProt's Protein Name: NAD-dependent protein deacylase. "The result in Fig. 2D confirmed that SeCobB was able to remove the acetyl group on Lys609 of SeAcs (lane 4), and rescued SeAcs activity. However, decrease in the acetylation level as well as the recovery of SeAcs activity by CobB treatment was inhibited remarkably in the presence of cAMP (lane 7)."	complete CACAO 12276
SALTY:ACSA		GO:0003987: acetate-CoA ligase activity	ECO:0000314:		F		Organism: Salmonella enterica (Salmonella typhimurium). Protein Name: Acetyl-coenzyme A synthetase (Acs). The control of Figure 1C shows that when molecules such as cAMP inhibit Acetyl-coenzyme A Synthetase, Acetate-CoA ligase activity is downregulated. Thus, SeAcs is involved with Acetate-CoA ligase activity.	complete CACAO 12268
SALTY:ACSA		GO:0051591: response to cAMP	ECO:0000314:		P		Organism: Salmonella enterica (Salmonella typhimurium). Protein Name: Acetyl-coenzyme A synthetase (Acs). "The potential inhibitory effect of cAMP on Acs was tested using a subsaturated concentration for each of the substrates. cAMP substantially inhibited SeAcs activity only in an enzymatic reaction system with a low concentration of ATP (Fig. 1C), suggesting cAMP inhibits SeAcs via an ATP-competitive mechanism."	complete CACAO 12318
SALTY:LYSAC		GO:0051591: response to cAMP	ECO:0000314:		P		Organism: Salmonella enterica (Salmonella typhimurium). Paper's Protein Name: Protein acetyltransferase OR Lysine acetyltransferase (Pat). UniProt's Protein Name: Protein lysine acetyltransferase. "As shown in Fig. 2C, SePat increases the acetylation level of SeAcs Lys609 in vitro (lane 4), and cAMP promotes Pat-dependent acetylation substantially (lane 7). The addition of cAMP to the acetylation assay system further decreases SeAcs activity, suggesting SeAcs acetylation promoted by cAMP also contributes to the inhibitory effect of cAMP on SeAcs."	complete CACAO 12271
SALTY:PRPE		GO:0050218: propionate-CoA ligase activity	ECO:0000314:		F		Organism: Salmonella enterica (Salmonella typhimurium). Paper's Protein Name: Propionyl-CoA synthetase (PrpE). UniProt's Protein Name: Propionate--CoA ligase. The control of Figure 6 shows that propionyl-CoA synthetase is involved with the activity of Propionate-CoA ligase.	complete CACAO 12278
SALTY:LCFA		GO:0004467: long-chain fatty acid-CoA ligase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Organism: Salmonella enterica (Salmonella typhimurium). Paper's Protein Name: Long-chain acyl-CoA synthetase (FadD). UniProt's Protein Name: Long-chain-fatty-acid--CoA ligase. The control of Figure 6 shows that long-chain acyl-CoA synthetase is involved with the activity of Acyl-CoA ligase.	complete CACAO 12279

References

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