Proline, structure

Fig. 9.4 Improvements in potency of N-tosyl-D-proline. Structural analyses revealed that the glutamate moiety from the mTHF cofactor could be appended to the hit from Tethering, and further elaboration led to a submicromolar inhibitor.

During the racemization of proline (structure VI), the chiral carbon must at some stage become trigonal. In accordance with a trigonal transition state, both structures VII and VIII bind 160 times more tightly than proline.14 15... 

Modification of the proline structure leads to more efficient chiral pyrrolidine catalysts, showing better selectivity and improved synthetic scope. 

Despite different sequences and repetitive motives, all gliadins have the same secondary structure of loose spirals which are a balanced compromise between the p-spiral and poly-L-proline structure (polyproline helix II) (Parrot et al., 2002), the balance is dependent on temperature, type of solvent, and hydration level (Miles et al., 1991). Similar sequences can be found in other proteins, mainly animal proteins such as elastin and collagen, and they are responsible for particular biomechanical properties connected to reverse P-spirals or p-sheet structures (Tatham and Shewry, 2000). 

Because of the similarity of the active sites of renin and HIV protease, the approach used was one that had been developed for renin inhibitors. HIV protease cleaves the linkage between two amino acids — phenylalanine (Structure 4.3) and proline (Structure 4.4). 

As briefly discussed above, another approach for the modiflcation of the proline structure is its transformation into a prolinamide bearing an appropriate subshtu-ent. Apart from simple prolinamide, which catalyzed the self-aldol reaction of... 

In the native protein these less stable ds-proline peptides are stabilized by the tertiary structure but in the unfolded state these constraints are relaxed and there is an equilibrium between ds- and trans-isomers at each peptide bond. When the protein is refolded a substantial fraction of the molecules have one or more proline-peptide bonds in the incorrect form and the greater the number of proline residues the greater the fraction of such molecules. Cis-trans isomerization of proline peptides is intrinsically a slow process and in vitro it is frequently the rate-limiting step in folding for those molecules that have been trapped in a folding intermediate with the wrong isomer. 

Glycine residues have more conformational freedom than any other amino acid, as discussed in Chapter 1. A glycine residue at a specific position in a protein has usually only one conformation in a folded structure but can have many different conformations in different unfolded structures of the same protein and thereby contribute to the diversity of unfolded conformations. Proline residues, on the other hand, have less conformational freedom in unfolded structures than any other residue since the proline side chain is fixed by an extra covalent bond to the main chain. Another way to decrease the number of possible unfolded structures of a protein, and hence stabilize the native structure, is, therefore, to mutate glycine residues to any other residue and to increase the number of proline residues. Such mutations can only be made at positions that neither change the conformation of the main chain in the folded structure nor introduce unfavorable, or cause the loss of favorable, contacts with neighboring side chains. 

Enzymes assist formation of proper disulfide bonds during folding Isomerization of proline residues can be a rate-limiting step in protein folding Proteins can fold or unfold inside chaperonins GroEL is a cylindrical structure with a... 

The structures and abbreviations for the 20 amino acids commonly found in proteins are shown in Figure 4.3. All the amino acids except proline have both free a-amino and free a-carboxyl groups (Figure 4.1). There are several ways to classify the common amino acids. The most useful of these classifications is based on the polarity of the side chains. Thus, the structures shown in Figure 4.3 are grouped into the following categories (I) nonpolar or hydrophobic... 

FIGURE 4.1 Anatomy of an amino acid. Except for proline and its derivatives, all of the amino acids commonly found in proteins possess this type of structure. 

The nonpolar amino acids (Figure 4.3a) include all those with alkyl chain R groups (alanine, valine, leucine, and isoleucine), as well as proline (with its unusual cyclic structure), methionine (one of the two sulfur-containing amino acids), and two aromatic amino acids, phenylalanine and tryptophan. Tryptophan is sometimes considered a borderline member of this group because it can interact favorably with water via the N-H moiety of the indole ring. Proline, strictly speaking, is not an amino acid but rather an a-imino acid. 

---