Acetyl AMP

Acetate and fatty acid activation enzymes - —acetylation of ATP with formation of acetyl AMP and PPi, replacement of AMP by CoA. 

Both reactions are freely reversible but the overall reaction is driven to the right by pyrophosphatase activity and/or by the re-phosphorylation of AMP. The short chain acyl-AMP is thought to be enzyme-bound. In the medium and long chain acyl-CoA synthetases, however, acyl-AMP is probably only formed as a side-product or with unphysiological or conformationally changed enzyme forms. This would explain why intermediary enzyme complexes were formed when medium and long chain synthetases were incubated with ATP and medium and long chain fatty acids but that acetyl-AMP could not be identified when the short chain synthetase was incubated with acetate. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Figure 21-6. Regulation of acetyl-CoA carboxylase by phosphorylation/dephosphorylation.The enzyme is inactivated by phosphorylation by AMP-activated protein kinase (AMPK), which in turn is phosphorylated and activated by AMP-activated protein kinase kinase (AMPKK). Glucagon (and epinephrine), after increasing cAMP, activate this latter enzyme via cAMP-dependent protein kinase. The kinase kinase enzyme is also believed to be activated by acyl-CoA. Insulin activates acetyl-CoA carboxylase, probably through an "activator" protein and an insulin-stimulated protein kinase.

Attention has been drawn to the potential of phosphoric acid anhydrides of nucleoside 5 -carboxylic acids (14) as specific reagents for investigating the binding sites of enzymes. For example, (14 B = adenosine) inactivates adenylosuccinate lyase from E. coli almost completely, but has little effect on rabbit muscle AMP deaminase. The rate of hydrolysis of (14) is considerably faster than that of acetyl phosphate, suggesting intramolecular assistance by the 3 -hydroxyl group or the 3-nitrogen atom. 

There are many examples of phosphorylation/dephosphorylation control of enzymes found in carbohydrate, fat and amino acid metabolism and most are ultimately under the control of a hormone induced second messenger usually, cytosolic cyclic AMP (cAMP). PDH is one of the relatively few mitochondrial enzymes to show covalent modification control, but PDH kinase and PDH phosphatase are controlled primarily by allosteric effects of NADH, acetyl-CoA and calcium ions rather than cAMP (see Table 6.6). 

The arsenal of plant defense peptides contains members capable of binding carbohydrate residues, namely /31-4 linked A -acetyl glucosamine residues that form the biopolymer chitin. The actual mode of action remains unclear. Antifungal and antimicrobial activity has been shown in vitro. For example Ac-AMP2 is a small disulfide-rich chitin-binding peptide isolated from the seeds of Amaranthus caudatus with antimicrobial activity. It differs from Ac-AMP 1 by one additional arginine residue at the C-terminus. The structure was determined by NMR and contains a cystine knot motif. Ac-AMP2 displays a so-called hevein domain partly... 

Figure 7.15 Inhibition of acetyl-CoA carboxylase by cyclic AMP dependent protein kinase and AMP dependent protein kinase the dual effect of glucagon. Phosphorylation of acetyl-CoA carboxylase by either or both enzymes inactivates the enzyme which leads to a decrease in concentration of malonyl-CoA, and hence an increase in activity of carnitine palmitoyltransferase-I and hence an increase in fatty acid oxidation. Insulin decreases the cyclic AMP concentration maintaining an active carboxylase and a high level of malonyl-CoA to inhibit fatty acid oxidation.

This enzyme [EC 6.2.1.1], also referred to as acetate-CoA ligase or acetate thiokinase, catalyzes the reaction of acetate, coenzyme A, and ATP to form acetyl-CoA, AMP, and pyrophosphate. The enzyme will also utilize propanoate and propenoate as substrates. 

AMP, and pyrophosphate (or, diphosphate). Propenoate can also act as the substrate. This enzyme is not identical with acetyl-CoA synthetase or with butyryl-CoA synthetase. 

Lent, B.A. Kim, K.-H. Phosphorylation and activation of acetyl-coenzyme A Carboxylase kinase by the catalytic subunit of cyclic AMP-dependent protein kinase. Arch. Biochem. Biophys., 225, 972-978 (1983)... 

Munday, M.R. Hardie, D.G. Isolation of three cyclic-AMP-independent acetyl-CoA carboxylase kinases from lactating rat mammary gland and characterization of their effects on enzyme activity. Eur. J. Biochem., 141, 617-627 (1984)... 

Ottey, K.A. Munday, M.R. Calvert, D.T. Clegg, R.A. Effect of anoxia on acetyl-CoA carboxylase activity possible role for an AMP-activated protein kinase. Biochem. Soc. Trans., 17, 350-351 (1989)... 

Vawas, D. Apazidis, A. Saha, A.K. Gamble, J. Patel, A. Kemp, B.E. Witters, L.A. Ruderman, N.B. Contraction-induced changes in acetyl-CoA carboxylase and 5 -AMP-activated kinase in skeletal muscle. J. Biol. Chem., 272, 13255-13261 (1997)... 

Additional information < >(< > not inhibitory AMP, ADP, ATP, GMP, GDP, GTP, cAMP, cGMP, acetyl-CoA, acetyl phosphate, glucose 6-phosphate, glucose 1-phosphate, fructose 1,6-diphosphate, t-histidine, o-histidine [14])... 

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