Acylation modification

In this chapter, we review the cloning of genes involved in the acyl modification of tylosin and the construction of strains that produce acyltylosins, including the important macrolide antibiotic AIV. 

II. CLONING GENES INVOLVED IN ACYL MODIFICATIONS OF MACROLIDES FROM S. THERMOTOLERANS... 

Geney R, Chen J, Ojima 1. Recent advances in the new generation taxane anticancer agents. Med. Chem. 2005 1 125-139. Appendino G, Bettoni P, Noncovich A, Sterner O, Fontana G, Bombardelli E, Pera P, Bernack RJ. Structure-activity relationship of ring C-secotaxoids. 1. Acylative modifications. J. Nat. Prod. 2004 67 184-188. 

Figure 27 N-acyl modifications to ManNAc affect its cellular toxicity. Changes in chain length and the addition of ketones affect metabolic incorporation of the compounds as well as cell viability. The lethal dose for the analogs decreases from left to right.

Wnt proteins are also acylated. The Wnt3a protein is modified by thioester-linked palmitate at a conserved cysteine residue and also by an unsaturated fatty acid, palmitole-ic acid, which is oxyester-linked to a conserved serine residue (R. Takada, 2006). Porcupine (pore), a member of the MBOAT family, is required for the O-acylation of Wnt3a. It is not clear whether pore or another acyltransferase carries out the 5-acyl modification. 

One of the key differences between RP2 and cofactor C is membrane association mediated via post-translational modification. Dual N-terminal acyl modification by myristoylation and palmitoylation target RP2 to the cytoplasmic face of the plasma membrane in cultured cells (Chappie et al., 2000) and in cells throughout the retina (Grayson et al., 2002). A pathogenic mutation AS6 (Rosenberg et al., 1999 Schwahn et al, 1998) in RP2 prevents the plasma membrane targeting of the protein (Chappie et al, 2000, 2002 Schwahn et al., 2001), illustrating that this post-translational modification is vital for the function of the protein in the retina. RP2 is not partitioned to either the apical or basolateral domains of polarized... 

Nishi, Y., Hiejima, H., Hosoda, H., Kaiya, H., Mori, K., Fukue, Y., Yanase, T., Nawata, H., Kangawa, K. Kojima, M. (2005). Ingested Medium-Chain Fatty Acids Are Directly Utilized for the Acyl Modification of Ghrelin. Endocrinol, 146(5), 2255-2264. 

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