Toxins that traverse cell membranes and either kill or deregulate cells

We know that these toxins are able to traverse membranes since their targets are intracellular. These proteins have common features: one component (usually described as the B fragment or subunit) binds to and interacts with a cell receptor and promotes the uptake of an active component (A fragment or subunit) in which resides the biological activity which confers toxicity. There are several ways in which one can subgroup these toxins.

1. Biologically, some kill cells (cytotoxic toxins) whereas others (sometimes called cvtotonic toxins) 'deregulate' cclls.

2. Some belong to a well-defined biochemical group recognized by their ability to cleave NAD+ into nicotinamide and ADP-ribose moieties. They are designated ADP-ribosyl (ADPR) transferases since they transfer ADPR to different target proteins.

3. The third possibility reflects the genetic origin of these toxins: (a) production from a single gene of a single peptide which undergoes post-trans-lational modification into A and B fragments that are covalently linked; (b) production from separate genes of A and B subunits which non-covalently associate into stable complexes, and (c) production from separate genes of different proteins which do not associate into stable complexes but which must act in concert to express toxicity. These are known as binary toxins.

Cytotoxic toxins

The classic example is diphtheria toxin (DT) made by Corynebacterium diphtheriae. This is the product of the tox gene (a constituent gene of p-phage) whose expression is regulated by [Fe]; the latter is a compressor of the tox gene. The processing, internalization and mode of action of DT is outlined in Figures 1-3.

A new and very exciting development is just beginning. For decades attempts have been made to make immunotoxins by coupling to native toxins antibodies specific to some surface antigen on tumor cells with as yet little practical success. However, Murphy's group in Boston, USA, have genetically engineered DT by substituting that portion of the DT structural gene encoding the native toxin receptor-binding domain with modified cDNA encoding one of a variety of cytokines and growth factors including IL-2, IL-4, IL-6, epidermal growth factor (EGF)

and a-melanocyte stimulating hormone (a-MSH). The resultant fusion toxin bears a new 'cellular address', but retains all of the other biological properties of the native DT molecule as well as a three-dimensional structure nearly identical with native DT. The IL-2 receptor fusion toxin has undergone phase I/II clinical trials for the treatment of IL-2 receptor-positive hematological malignancies (and other IL-2-related conditions) and has been shown to be safe and well-tolerated. A new era of 'magic bullets'?

Pseudomonas exotoxin A (PsA) acts in a near identical manner to DT on NAD' and EF2, despite the fact that there are no sequence homologies or serological cross-reactivites between DT and PsA. For DT, HeLa cells are more susceptible than mouse cells; the converse is true for PsA.

Other ADP-ribosylating toxins and their targets are: Pseudomonas exotoxin S (erythrocyte proteins -not necessarily the main target); cholera and E. coli LT toxins (as subunits of G-regulator proteins); pertussis toxin (not the invasive adenylate cyclase described below - c^ subunit of G-regulator proteins); botulinum C2 toxin (not a neurotoxin; nonmuscle actin). Shiga toxin [Shigella dysenteriae) has an AB5 (B5 is a homopolymer)-type structural arrangement similar to cholera toxin. Certain bio-types of E. coli make Vero toxins (VTs; or Shiga-like toxins (SLTs)) which are identical (SLT1) or near identical (SLT2) with Shiga toxin. The role of Shiga

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