Mini-Reviews in Medicinal Chemistry, Volume 4, No. 5, 2004
Contents
Ribosome-Inactivating
Proteins
Executive
Editor: Fiorenzo Stirpe
Description, Distribution, Activity and
Phylogenetic Relationship of Ribosome-Inactivating Proteins in Plants, Fungi
and Bacteria Pp. 461-476
Tomas Girbes, Jose Miguel Ferreras,
Francisco Javier Arias and Fiorenzo Stirpe
The Structure of Ribosome Inactivating
Proteins Pp. 477-486
Jon
D. Robertus and Arthur F. Monzingo
Genetics of Ribosome-Inactivating Proteins Pp. 487-492
Martin
R. Hartley and J. Michael Lord
The Genetics and Properties of Cereal
Ribosome-Inactivating Proteins Pp.
493-503
Mario
Motto and Elisabetta Lupotto
Ribosome-Inactivating Proteins: Entry into
Mammalian Cells and Intracellular Routing Pp. 505-512
Lynne
M. Roberts and J. Michael Lord
Cytotoxicity and Toxicity to Animals and
Humans of Ribosome-Inactivating Proteins Pp. 513-521
Maria
Giulia Battelli
Antiviral Activity Of Ribosome Inactivating
Proteins In Medicine Pp.
523-543
Bijal
A. Parikh and Nilgun E. Tumer
Immunotoxins
and Other Conjugates: Preparation and General Characteristics Pp. 545-562
Giulio
Fracasso, Giuseppe Bellisola, Deborah Castelletti, Giuseppe Tridente and Marco
Colombatti
Immunotoxins and Other Conjugates:
Pre-clinical Studies Pp.
563-583
A. Bolognesi and L. Polito
Immunotoxins and Neuropeptide-Toxin
Conjugates Experimental Applications Pp. 100%-595
Dougles A. Lappi and Ronald G. Wiley
Abstracts
[Back to top] Description, Distribution, Activity and
Phylogenetic Relationship of Ribosome-Inactivating Proteins in Plants, Fungi
and Bacteria
Ribosome-Inactivating
Proteins (RIPs) are enzymes that trigger the catalytic inactivation of
ribosomes and other substrates. They are present in a large number of plants and
have been found also in fungi, algae and bacteria. RIPs are currently
classified as type 1, those formed by a single polypeptide chain with the
enzymatic activity, and type 2, those formed by 2 types of chains, i.e. A
chains equivalent to a type 1 RIPs and B chains with lectin activity. Type 2
RIPs usually contain the formulae A-B, (A-B)2 and less frequent (A-B)4 and polymeric forms of
type 2 RIPs lectins. RIPs are broadly distributed in plants, and are present
also in fungi, bacteria, at least in one alga; recently RIP-type activity has
been described in mammalian tissues. The highest number of RIPs has been found
in Caryophyllaceae, Sambucaceae, Cucurbitaceae, Euphorbiaceae,
Phytolaccaceae and Poaceae. However there are no systematic
screening studies to allow generalisations about occurrence. The most known
activity of RIPs is the translational inhibitory activity, which seems a
consequence of a N-glycosidase on the 28 S rRNA of the eukaryotic ribosome
that triggers the split of the A4324 (or an equivalent base in other ribosomes),
which is key for translation. This activity seems to be part of a general
adenine polynucleotide glycosylase able to act on several substrates other than
ribosomes, such as tRNA, mRNA, viral RNA and DNA. Other enzymatic activities
found in RIPs are lipase, chitinase and superoxide dismutase. RIPs are
phylogenetically related. In general RIPs from close families share good amino
acid homologies. Type 1 RIPs and the A chains of type 2 RIPs from Magnoliopsida
(dicotyledons) are closely related. RIPs from Liliopsida (monocotyledons) are
at the same time closely related and distant from Magnoliopsida. Concerning the
biological roles played by RIPs there are several hypotheses, but the current
belief is that they could play significant roles in the antipathogenic (viruses
and fungi), stress and senescence responses. In addition, roles as antifeedant
and storage proteins have been also proposed. Future research will approach the
potential biological roles played by RIPs and their use as toxic effectors in
the construction of immunotoxins and conjugates for target therapy.
[Back to top] The Structure of Ribosome Inactivating
Proteins
Ribosome Inactivating Proteins, RIPs, depurinate an
invariant adenine from the 28S rRNA of eukaryotic ribosomes; they have evolved
to near enzymatic perfection for this task. The N-glycosidase fold is conserved
in plant and bacterial enzymes. RIPs can form complexes with cell surface
recognition proteins that dramatically increase the cytotoxicity of the
molecule.
[Back to top] Genetics of Ribosome-Inactivating Proteins
Ribosome-inactivating proteins (RIPs) are a heterogeneous
group of enzymes found mainly in plants and a few bacteria that possess
N-glycosidase activity on ribosomes and a related polynucleotide adenosine
glycosidase activity on naked nucleic acids. They encompass single enzymatic
chains, heterodimeric toxic lectins and related agglutinins. Plants commonly
produce several RIP isoforms encoded by multi-gene families. The toxic lectins
possess adaptations related to their cytotoxic role.
[Back to top] The Genetics and Properties of Cereal
Ribosome-Inactivating Proteins
Plants contain proteins that are capable of inactivating
ribosomes, commonly referred to as Ribosome Inactivating Proteins RIPs). These particular plant proteins have
received attention in biological and biomedical research because of their
unique biological activities towards animals and human cells as cellkilling
agents. Some of the best-characterised RIPs have been isolated from exotic
plants, but they have also been found in cereals and other food crops. Cereals
contain, in general, RIPs in the endosperm protein pool: they share a high
similarity with all the other RIPs retaining, however, characteristic features
forming a distinct class which diversified significantly during evolution. They
appear to be involved in quite different physiological roles, such as defence
against pathogens and/or involved in regulatory and developmental processes.
This review aims to provide a critical assessment to work related to cereal RIP
with particular emphasis to the maize RIPs.
[Back to top] Ribosome-Inactivating Proteins: Entry into
Mammalian Cells and Intracellular Routing
To catalytically-modify ribosomes in vivo, ribosome-inactivating proteins produced by plants must enter susceptible mammalian cells in order to reach their substrates in the cytosol. This review primarily focuses on the biosynthesis, mechanism of cell entry and intracellular trafficking of ricin, the most thoroughly studied ribosome-inactivating protein in this respect.
[Back to top] Cytotoxicity and Toxicity to Animals and
Humans of Ribosome-Inactivating Proteins
The toxicity to cells and animals of type 1 and toxic and non-toxic type 2 Ribosome-Inactivating Proteins (RIP) is discussed in correlation with their catalytic activity, resulting in ribosome inactivation and apoptosis. The symptoms and histopathological lesions induced by RIP to animals and humans is also reviewed.
[Back to top] Antiviral Activity
Of Ribosome Inactivating Proteins In Medicine
Bijal A. Parikh and Nilgun E. Tumer
Pokeweed antiviral protein and several other ribosome inactivating proteins are effective against a broad range of viruses. Recent results have shown that their enzymatic activity is not limited to depurination of the large rRNA, they can depurinate other nucleic acids, including viral RNAs. Antiviral activity of RIPs is summarized here in light of their novel activities and recent developments in the field.
[Back to top] Immunotoxins and Other Conjugates:
Preparation and General Characteristics
Giulio
Fracasso, Giuseppe Bellisola, Deborah Castelletti, Giuseppe Tridente and Marco
Colombatti
Targeted toxins represent an
invaluable tool offering a wide range of potential applications, both in
experimental models and in the clinics. Here we will review several aspects
related to the preparation and properties of carrier molecule-toxin
heteroconjugates and fusion toxins.
[Back to top] Immunotoxins and Other Conjugates:
Pre-clinical Studies
A wide variety of conjugates
containing RIPs, of either chemical or recombinant type, have been made and
tested against dangerous cells in vitro and in animal models. Many of
these pre-clinical studies will be
reviewed here dividing them on the basis of the target cell and the surface
molecule specifically recognized.
[Back to top] Immunotoxins and Neuropeptide-Toxin Conjugates Experimental Applications
The use of targeted toxins in research applications has
recently grown considerably. The ability to remove a few specific cells, even
when surrounded by different populations, has given scientists a powerful tool
for the understanding of systems biology. The use of targeted toxins in
research is rich and varied; here we limit ourselves to describe some of those
exciting results that researchers have made in the neurosciences.