Cyclic polypeptide complex

Capreomycin is a cyclic polypeptide complex antibiotic having a structure very much similar to viomycin, and produced by Streptomyces capreolus as a mixture of about four different components. It exerts its bacteriostatie aetion against certain mycobacterial strains, such as M. tuberculosis M. bovis M. kansasii, andM. avium by an unknown mechanism of action. However, its pharmacological and antibacterial activities are quite akin to the aminoglycosides. 

Macrocyclic compounds with ion-chelating properties occur naturally and often function as ionophores, translocating ions across biological membranes many of these compounds are small cyclic polypeptides. Some natural carboxylic polyethers are selective for Li+ and are, therefore, ionophores for Li+. Monensin, shown in Figure Id, is a natural ionophore for Na+ but it will also complex with Li+ and it has been shown to mediate the transport of Li+ across phospholipid bilayers [21]. It has been proposed that synthetic Li+-specific ionophores have a potential role as adjuvants in lithium therapy, the aim being to reduce the amount of... 

Natural products derived from amino acids form a broad and divergent group, including simple amino acid derivatives, alkaloids, and small, often cyclic, polypeptides. Simple amino acid derivatives, which are not uncommon in algae, are often oxidation or rearrangement products of one of the 20 common amino acids. Alkaloids and polypeptides are more complex in their structural modifications. 

One of the aspects of structural complexity in biomolecules is that of stereochemistry. To the increase in stereochemical complexity when going to larger biomolecules correspond new stereochemical features and properties. Thus, the concepts of cycloenantiomerism, cyclodiastereoisomerism and cyclostereoisomerism have been introduced by Prelog and collaborators [118-120] to describe stereochemical features of cyclic molecules displaying 2n centers of chirality, e.g., cyclic polypeptides. 

Cyclosporine provides maintenance immunosuppression by inhibition of the activation of T lymphocytes via a multifaceted mechanism. The drug, a fat soluble 11 amino acid cyclic polypeptide, crosses the lymphocyte membrane freely where it forms a pharmacologically active complex with the intracellular immunophilin receptor cyclophilin. This complex, but not cyclosporine by itself, inhibits the Ca /calmodulin-activated form of serine/threonine phosphatase calcineurin, thereby inhibiting the activation of NFAT cells. The latter action is considered to be the key step... 

Cyclic polypeptides [69] can interact with both cations through C=0 moieties and anions through N-H moieties (Fig. 17). In structures 6 and 7, both carbonyl and amide groups are nearly on the same cylindrical surface, i.e., nearly parallel to the principal axis. Upon complexation with an ion, the cyclic peptides are found to have two types of binding one at the center ( where n... 

NRPSs have made significant advances in the synthesis of cyclic polypeptides and the ability to introduce modified amino adds will assist in the development of scaffolds for biomaterials. However, NRPSs produce low molecular weight polypeptides and require large enz)nnatic complexes, which are difficult to use in large-scale production of polypeptides. 

Albomycin an antibiotic synthesized by Actinomyces subtropicus. A. is a cyclic polypeptide containing a pyrimidine base (cytosine) and 4.16% Fe in the form of a hydroxamate-Fe(IIl) complex (Fig.). It is one of the sideromycins (similar to, and possibly identical to, grisein), and it interferes with iron metabolism as an antimetabolite of the sideramines. A. is effective against both Gram-positive and Gram-negative bacteria, and inhibits the aerobic metabolism of Staphylococcus aureus and E. colt... 

We may now examine how a dissymmetric macromolecular complex of proteins, found in nature, is responsible for the synthesis of this cyclic polypeptide without the need of ribosomes. This process, which occurs only in simple organisms like bacteria, was deciphered by the biochemist F. Lipmann, from Rockefeller University. 

Many biochemical and biophysical studies of CAP-DNA complexes in solution have demonstrated that CAP induces a sharp bend in DNA upon binding. This was confirmed when the group of Thomas Steitz at Yale University determined the crystal structure of cyclic AMP-DNA complex to 3 A resolution. The CAP molecule comprises two identical polypeptide chains of 209 amino acid residues (Figure 8.24). Each chain is folded into two domains that have separate functions (Figure 8.24b). The larger N-terminal domain binds the allosteric effector molecule, cyclic AMP, and provides all the subunit interactions that form the dimer. The C-terminal domain contains the helix-tum-helix motif that binds DNA. 

It has been demonstrated that phosphorylation of LHC causes the detachment of a fraction of it from PS II and its lateral migration in the membrane to become incorporated into PS I [134-136]. It has indeed been shown that the fluorescence quenching caused by LHC phosphorylation is qualitatively different from spillover, because only LHC is quenched, not PS II [136], and Fq as well as are quenched [136,137]. The phosphorylation of LHC and/or of other thylakoid polypeptides may have more complex effects, and their interactions are far from being understood. It has been reported that protein phosphorylation enhances PS I-de-pendent cyclic photophosphorylation even under light saturation conditions [133], which could not be explained merely on the basis of PS I antenna enlargement. 

Additional polypeptides ascribed to the Cyt b-f complex are a bound form of ferredoxin-NADP reductase (FNR) [99] and one or more smaller polypeptides [100]. An association of the complex with ferredoxin-NADP reductase may be expected in view of the reported role of FNR in cyclic electron flow from PS I to the Cyt complex [101]. FNR remains associated with the complex during the early stages of the purification of the complex but there is no evidence that it is an intrinsic component of the complex necessary for plastoquinol-plastocyanin oxido-reductase. The presence of small polypeptides in the complex requires further investigation. Polypeptides of about 5 kDa have been reported to be associated with the spinach complex [100]. 

---