**1. Introduction**

106 Biochemistry

Yayoshi-Yamamoto, S.; Taniuchi, I. & Watanabe, T. (2000). FRL, a novel formin-related

*Molecular and cellular biology*, Vol.20, No.18, pp. 6872–6881, ISSN 0270-7306. Yeh, E.T.; Zhang, S.; Wu, H.D.; Korbling, M.; Willerson, J.T. & Estrov, Z. (2003).

Youn, T.; Kim, S.A. & Hai, C.M. (1998). Length-dependent modulation of smooth muscle

Zeile, W.L; Purich, D.L. & Southwick, F.S. (1996). Recognition of two classes of oligoproline

Zhong, J.C.; Ye, J.Y.; Jin, H.Y.; Yu, X.; Yu, H.M.; Zhu, D.L.; Gao, P.J.; Huang, D.Y.; Shuster,

Zou, L.; Jaramillo, M.; Whaley, D.; Wells, A.; Panchapakesa, V.; Das, T. & Roy, P. (2007)

*Journal of cell biology*, Vol.133, No.1, pp. 49-59, ISSN 0021-9525.

*journal of cancer*, Vol. 97, No.10, pp. 1361-1371, ISSN 0007-0920.

Vol.108, No.17, pp. 2070 –2073, ISSN 0009-7322.

pp. 6161–6165, ISSN 0027-8424.

No.1-3, pp. 90-97, ISSN 0167-0115

protein, binds to Rac and regulates cell motility and survival of macrophages.

Transdifferentiation of human peripheral blood CD34+-enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. *Circulation,*

activation: effects of agonist, cytochalasin, and temperature. *American journal of physiology. Cell physiology*. Vol.274, No.6 Pt.1, pp. C1601–C1607, ISSN 0002-9513. Zang, Z.; Vuori, K.; Reed, J.C. & Ruoslahti, E. (1995). The alpha 5 beta 1 integrin supports

survival of cells on fibronectin and up-regulates Bcl-2 expression. Proceedings of the National Academy of Sciences of the United States of America, Vol.92, No.13,

sequences in profilin-mediated acceleration of actin-based Shigella motility. *The* 

M.; Loibner, H.; Guo, J.M.; Yu, X.Y.; Xiao, B.X.; Gong, Z.H.; Penninger, J.M. & Oudit, G.Y. (2011). Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. *Regulatory Peptides*. Vol.166,

Profilin-1 is a negative regulator of mammary carcinoma aggressiveness. *British* 

Protein toxins are prominent virulence factors in many pathogenic bacteria. While toxins of Gram-positive bacteria do not generally require activation, many toxins of the Gramnegatives are translated into an inactive form and require a processing step.

The most common such step involves a proteolytic cleavage to generate the active form, especially in those toxins with enzymatic activity. Toxins are activated by proteolysis in a variety of ways: As examples, the anthrax toxin is proteolyzed after its interaction with the receptor on the target cell to promote the formation of a prepore (van der Goot & Young, 2009); the toxic subunit of the *Vibrio cholerae* toxin (CT) is posttranslationally modified through the action of a *V. cholerae* protease that generates two fragments, one containing the toxic activity and the other serving to interact with the binding domain (Sanchez & Holmgren, 2011); finally, the toxins that are synthesized as a single polypeptides must be separated by proteolytic cleavage to generate a catalytic, a transmembrane, and a receptor-binding domain—a salient example here being the diphtheria toxin (Murphy, 1996).

Another processing step involves the acylation of proteins, which substitution is achieved by various mechanisms that differ according to the particular fatty acid transferred, the modified amino acid, and the fatty-acyl donor. Myristate and palmitate are the most common fatty acids cross-linked to proteins. Proteins sorted to the bacterial outer membrane or to the eukaryotic plasma membrane undergo processing in which an acyl group is attached to the N-terminal amino acid. In prokaryotes, acyltransferase, lipases, or esterases use catalytic mechanisms involving ester-linked acyl groups attached to serine and cysteine residues; while eukaryotic proteins utilize ester-linked palmitoylation and ether-linked prenylation of cysteine residues for membrane sorting and protein-protein interaction (Stanley *et al.*, 1998).

The pore-forming **α-hemolysin (HlyA)** of *Escherichia coli,* a member of the RTX toxins, represents a unique class of bacterial toxins that require for activation a posttranslational modification involving a covalent amide linkage of fatty acids to two internal lysine residues (Stanley *et al.*, 1998). In general, protein acylation is divided into labile modifications of internal regions and stable modifications at the N and C termini. By contrast, the mechanism of stable internal acylation of HlyA represents a unique example among prokaryotic proteins, thus generating interest in its study and discussion. After introducing HlyA, its synthesis, posttranslational modification, secretion, and activity; this chapter will focus on the role that covalently bound fatty acids play in the toxin's mechanism of action.

In recent decades, scientific advances have permitted the manipulation of toxins by using different strategies for directing toxic moieties to diseased cells and tissues. The end of the chapter will involve a discussion of this so-called *toxin-based therapy* and the potential use of HlyA in that modality.
