Proline interconversion

PROLINE REDUCTASE L-Proline to D-proline interconversion, PROLINE RACEMASE PROLIPOPROTEIN SIGNAL PEPTIDASE PROLYL 3-HYDROXYLASE PROLYL 4-HYDROXYLASE PROLYL ISOMERASE... 

Bertolo, R.F., J.A. Brunton, P.B. Pencharz, and R.O. Ball, 2003. Arginine, ornithine, and proline interconversion is dependent on small intestinal metabolism in neonatal pigs. Am. J. Physiol 284, E915-922. 

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

This enzyme [EC 5.1.1.8] catalyzes the interconversion of tran5 -4-hydroxy-L-proline to d5 -4-hydroxy-D-proline. It also interconverts rrans-4-hydroxy-D-proline and cis-4-hydroxy-L-proline. 

The energy barrier for internal rotation in dipeptides is generally high (89.6 kJ mor in L-hystidyl-L-proline) (82MI6) but decreases when the dipeptide unit is introduced in internal positions of a longer sequence. This is seen (82MI6), for example, in the octapeptide angiotensin II, in which the L-hystidyl-L-prolyl unit is in position 6 or 7, and the interconversion rate becomes 70 times faster than in the isolated dipeptide. 

Refolding is generally found to proceed by a series of exponential phases. Many of these exponentials are a consequence of cis-trans isomerization about peptidyl-prolyl bonds.14,15 The equilibrium constant for the normal peptide bond in proteins favors the trans conformation by a factor of 103-104 or so. The peptidyl-prolyl bond is an exception that has some 2-20% of cis isomer in model peptides (see Chapter 1, Figure 1.3). Further, it is often found as the cis isomer in native structures. (Replacement of ds-prolines with other amino acids by protein engineering can retain the cis stereochemistry.16) The interconversion of cis to trans in solution is quite slow, having half-lives of 10-100 s at room temperature and neutral pH. This has two important consequences. First, a protein that has several... 

We have seen that the form I —> form II interconversion may take place along different pathways depending on the solvent system, with differing over-all mutarotation kinetics. In acetic acid the apparent order of the forward mutarotation reaction is 1.33 (0). It will be seen from Eq. (8) that in this case K t) should decrease with time, in agreement with the experimental observations. When 0 = 1, the mutarotation proceeds with first-order kinetics. This behavior is seen in the reverse mutarotation of poly-L-proline II in acetic acid-propanol. When /3 < 1, K (t) increases with time. This situation obtains in the initial stage of the forward mutarotation in acetic acid-water solvent which proceeds with zero-order kinetics. 

The right panel in Figure 3 depicts 1/1(0) for (+)-catechin in mixtures of trifluoroethanol and 1-propanol that contain poly(L-proline) at a concentration of 0.90 mg/ml. In pure trifluoroethanol 1/1(0) is slightly less than one. At the opposite extreme of solvent composition, I/l(0) is greater than one and increases over a period of several days. The greatest sensitivity of 1/1(0) to solvent composition occurs near 25 75 trifluoroethanol 1-propanol, which is where the Form I - Form II interconversion is detected by circular dichroism. Measurements of the fluorescence of (+)-catechin in the mixed solvents, but in the absence of poly(L-proline), show no unusual dependence of emission on solvent. 

Extensive mapping of the conformational surface of c[Pro-pro-Pro-pro] with DFT calculations by Che and Marshall (124) showed that a set of eight distinct amide-bond conformers and their interconversions (Fig. 9) based on the number and location of cis- or tmns-amide bonds tttt, or all trans cccc, or all cis tctc ctct, tccc, cttt, ttcc, and cctt) were accessible. Individual conformers could be selectively stabilized by use of azaproline in which the alpha carbon of proline was replaced by nitrogen and other proline analogs. 

Thrl67 bond in the cis Prol67Thr TEM-1 /J-lactamase variant is also characterized by a rate constant between 1 x 10-3 s-1 and 4 x 10 3 s-1 for the trans to cis interconversion [26]. Therefore the trans to cis isomerization can be rate-limiting in protein folding under native-like conditions, as was shown for a proline-free variant of the a-amylase inhibitor tendamistat [27]. This seems to be proven in the discovery of a novel protein dass, the secondary amide peptide cis/trans isomerases (APIases), which can accelerate interconversion of these peptide bonds conformers [28],... 

The enzyme exists in two different protonation states of the active site cysteines, each binding a different enantiomer. Conversion between enantiomers can be through the racemization path (upper manifold of Fig. 7.16) or through direct proton exchange with water (lower manifold of Fig. 7.16). Knowles and coworkers found that interconversion of enzyme protonation states was kinetically significant [82]. This was determined by measuring rates of tritiated proline washout as a function of the proline concentration. It was found that higher concentrations of proline promote slower washout of the Ca proton. Additional support for the rela-... 

Figure 1. Peptidyl prolyl isomerases catalyze the interconversion of c/s-and frans-amide bond rotamers adjacent to proline residues in peptidic substrates.

Proline-derived oxazaborolidines 45 have shown to be effective pre-catalysts with triflic acid as an activator to generate cationic Lewis acids.18,15 The optimal proportions of 45 and triflic acid was found to be 1.2 1. Protonation of 45 produced a 1.5 1 mixture of 46 and 47 as determined by low temperature H NMR. Their interconversion at low temperature (-80 °C) is slow on the NMR timescale. However, this interconversion increases as the temperature rises and at 0 °C this becomes rapid (Tc). Phenyl or o-tolyl were determined to be the best substituents for the R group in 45. For the Ar group of 45, phenyl and 3,5-dimethylphenyl were determined to be optimal. 

The retro synthetic pathway is outlined in Scheme 49 and starts with the simplification of the TAN1251A again to the known intermediate 119, whose first conversion into the alkaloid had been reported by the same authors [63], The target compound 119, in turn, can be prepared from 126 also following their known protocol. Compound 126 should be obtained from 156 via installation of an azide group and A-alkylation. Disassembly of the cyclohexanone ring from 156 in a retrosynthetic sense leads to keto aldehyde 155, which may be prepared by alkylation of proline 154 followed by some functional group interconversion steps. 

---