Lysine acetylation system

Fig. 4.1. Fundamentals of the ubiquitin system. Adapted from Ref [5]. Figure 4.1 shows the fundamentals of the ubiquitin system. (1) Ubiquitin is synthesized in linear chains or as the N-terminal fusion with small ribosomal subunits that are cleaved by de-ubiquitylating enzymes to form the active protein. Ubiquitin is then activated in an ATP-dependent manner by El where a thiolester linkage is formed. It is then transthiolated to the active-site cysteine of an E2. E2s interact with E3s and with substrates and mediate either the indirect (in the case of HECT E3s) or direct transfer of ubiquitin to substrate. A number of factors can affect this process. We know that interactions with Hsp70 can facilitate ubiquitylation in specific instances and competition for lysines on substrates with the processes of acetylation and sumoylation may be inhibitory in certain instances. (2) For efficient proteasomal targeting to occur chains of ubiquitin linked internally through K48 must be formed. This appears to involve multiple...

Stadtman has demonstrated (42) the conversion of carbamyl phosphate and acetate to acetyl phosphate, catalyzed either by a crude lysine system or by a purified acetate kinase from C. sticklandii. ADP and... 

Several of the proteins of the Golgi transport system are AT-acetylated at either the amino terminal or the e-amino group of a lysine residue. Acylation may be either cotranslational or posttranslational. Amino terminal acylation protects the proteins from degradation, and various acylations are required for the assembly of multisubunit membrane proteins and transport of glycoproteins through the Golgi. 

The first enzyme in the system catalyzes the reaction of TPP with pyruvate to form the same resonance-stabilized carbanion formed by pyruvate decarboxylase and by the enzyme in Problems 8 and 9. The second enzyme of the system (E2) requires lipoate, a coenzyme that becomes attached to its enzyme by forming an amide with the amino group of a lysine side chain. The disulfide linkage of lipoate is cleaved when it undergoes nucleophilic attack by the carbanion. In the next step, the TPP carbanion is eliminated from the tetrahedral intermediate. Coenzyme A (CoASH) reacts with the thioester in a transthioesterification reaction (one thioester is converted into another), substituting coenzyme A for dihydrolipoate. At this point, the final reaction product (acetyl-CoA) has been formed. However, before another catalytic cycle can occur, dihydrolipoate must be oxidized back to lipoate. This is done by the third enzyme (E3), an FAD-requiring enzyme (Section 25.3). Oxidation... 

Nacystelyn, a lysine salt of N-acetyl-c-cysteine augmenting cellular antioxidant defence in vitro (Gillissen et al. 1997), abolished the transcriptional activation of interleukin-8 in an IL-8-chlor-amphenicol acetyltransferase reporter system, transfected into A549 cells (Antonicelli et al. 2002). 

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