Enzymes, adenylate-forming

Forskolin is an activator of the enzyme adenylate cyclase which has therapeutic utility. Outlined below are stereocontrolled routes to racemic and natural chiral forms of forskolin derived by multistrategic retrosynthedc analysis. 

Conti, E., Franks, N. P., and Brick, P. (1996). Crystal structure of firefly luciferase throws light on a superfamily of adenylate-forming enzymes. Structure 4 287-298. 

After the formation of an acyl adenylate, the similarities between MoeB and El appear to come to an end (Figure 3.2B). In the El enzymes an active-site cysteine residue attacks the ubiquitin adenylate forming the El-ubiquitin thioester. E. coli MoeB contains nine cysteine residues, four of which are involved in coordinating the zinc atom. Sequence alignments show that among the remaining cysteines... 

Relaxation of smooth mnscles is controlled by the concentration of cyclic GMP in the muscle. This is regulated by the activities of the enzyme that forms cyclic GMP (i.e. gnanyl cyclase) and the enzyme that degrades cyclic GMP, that is, cyclic GMP phosphodiesterase (see Box 12.2). This is analogons to the enzyme system that regulates the concentration of cyclic AMP, by the activities of adenyl cyclase and phosphodiesterase ... 

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

Cyclic-AMP is formed from ATP in a reaction catalyzed by the enzyme adenylate cyclase. Assume that adenylate cyclase acts as a base to remove a proton from the 3 -hydroxyl group of ATP and write a mechanism for the formation of cAMP. 

K Turgay, M Krause, MA Marahiel. Four homologous domains in the primary structure of GrsB are related to domains in a superfamily of adenylate-forming enzymes. Mol Microbiol 6 529-546, 1992. 

An early emergence of adenylate-forming enzymes can also explain the wide diversification of this family of enzymes [175], many of which are now capable of reacting with carboxylic acids without a-amino group (essential in the hypothetical early mechanism using NCAs as substrates, but then useless) and which is involved in many different biosynthetic pathways. 

Stuible, H.R, Buttner, D., Ehlting, J., Hahlbrock, K. and Kombrink, E. (2000) Mutational analysis of 4-coumarate CoA ligase identifies functionally important amino acids and verifies its close relationship to other adenylate-forming enzymes. FEES Lett., 467,117-22. 

Why is AMP and not ADP the positive regulator of phosphofructokinase When ATP is being utilized rapidly, the enzyme adenylate kinase (Section 9.4) can form ATP from ADP by the following reaction ... 

Paul Berg showed that the activation of a fatty acid is accomplished in two steps. First, the fatty acid reacts with ATP to form an acyl adenylate. In this mixed anhydride, the carboxyl group of a fatty acid is bonded to the phosphoryl group of AMP. The other two phosphoryl groups of the ATP substrate are released as pyrophosphate. The sulfhydryl group of CoA then attacks the acyl adenylate, which is tightly bound to the enzyme, to form acyl CoA and AMP. 

Let us look at the mechanism of joining, which was elucidated by I. Robert Lehman (Figure 27.29). ATP donates its activated AMP unit to DNA ligase to form a covalent enzyme-AMP (enzyme-adenylate) complex in which AMP is linked to the e-amino group of a lysine residue of the enzyme through a phosphoamide bond. Pyrophosphate is concomitantly... 

Cyclic AMP is formed from ATP by the enzyme adenylate cyclase, which is situated on the inner cell membrane, and it is this enzyme that is responsible for the amplification of the hormone signal, because just one enzyme molecule, when activated by the hormone-receptor complex, can of course produce many cyclic... 

Branchini BR, Murtiashaw MH, Magyar RA, Anderson SM. The role of lysine 529, a conserved residue of the acyl-adenylate-forming enzyme superfamily, in firefly luciferase. Biochemistry 2000 39 5433-40. 

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