Phenylalanine gramicidin

Other workers began to study the structure of gramicidin. Christensen and coworkers12 isolated crystalline tryptophane and leucine from a hydrolysate. They found no evidence for a fatty acid component and established that phenylalanine, proline and hydroxyproline were absent from a hydrolysate. These workers isolated alanine diox-pyridate from a hydrolysate and also established that gramicidin contained a compound with vicinal hydroxy and amino groups. They speculated that this compound might be serine or isoserine and proposed that gramicidin contains two tryptophane, 2 leucine, 2 or 3 alanine and 1 hydroxyamino residues or a multiple of this composition. 

An adenylation domain from the gramicidin S synthetase provided the first atomic resolution structural information for an NRPS domain (Figure 11 (a)). The excised protein is part of the first module of the synthetase. The domain is responsible for both activating the amino acid phenylalanine and loading the building block onto the adjacent PCP domain. The structure demonstrated that A domains share a common... 

E Conti, T Stachelhaus, MA Marahiel, P Brick. Structural basis for the activation of phenylalanine in the non-ribosomal biosynthesis of gramicidin S. EMBO J 16 4174-4183, 1997. 

Figure 24 Stereo views of (A) computed39 179 and (B) X-ray180 structures of gramicidin S, showing (among other things) a hydrogen bond between the ornithine side chain and the phenylalanine backbone carbonyl group.

In most peptides synthetases an epimerization domain that mediates D-amino acid incorporation is embedded within the module. Thus, L-amino acids are substrates of the synthetase and in situ epimerization occurs during peptide chain elongation. The first module of gramicidin S synthetase from Bacillus brevis is a well studied example [39]. This module recognizes L-phenylalanine, and the tightly bound intermediate is epimerized to fhe D-Phe-enzyme com-... 

Gramicidin S is an antibiotic produced by a strain of bacteria. It is a cyclic dec-apeptide. Notice that it contains the amino acids L-ornithine (L-Orn), o-omithine (D-Orn), and also o-phenylalanine. Ornithine is not listed in Table 23.1 because it occurs rarely in nature. Ornithine resembles lysine, but has one less methylene group in its side chain. 

The carboxylic acid analogues lacking the a-amino group are not activated by gramicidin S-synthetase. Hydrocinnamic acid, the analogue of phenylalanine, inhibits reaction 1 non-competitively. This compound most likely does not bind to the reaction center of GS 2 (2). Cyclopentane carboxylic acid and isocapronic acid show a very weak inhibition of the L-Pro resp. L-Leu activation. Carboxylic acid analogues of L-Orn (5-aminovaleric acid as well as 4-aminobutyric acid and 6-aminocapronic acid with a shortened or extended chain) do not appreciably affect reaction 4. 

J. Vater, and H. Kleinkauf, A further characterization of phenylalanine racemase, the light enzyme of gramicidin S-synthetase, Biochim. Biophys. Acta 429, 1062 (1976). 

Stein T, Kluge B, Barer ], Franke P, Otto A, Wittmann-Licbold B. Gramicidin S synthetase I (phenylalanine racemase). a prototype of amino acid racemascs eomaining the ccrfactor 4 -pKosphopantetheine, Biochem 1995 34 4633-4642. 

Vater J, Kleinkauf, H Gramicictin S-synthetase A funher chatacteriMtion of phenylalanine racemase, the light emyme of gramicidin S-synchetase. Biochim Biophys Acta 1976 429 1062-1072. 

Dubos showed that tyrothricin could be separated into two components, gramicidin and tyrocidine. Craig showed that tyrocidine could be resolved into three components, tyrocidines A, B and C. Tyrocidine A has the structure XI and t5nrocidine B differs from XI only in containing an L-tryptophan residue in place of an L-phenylalanine residue . 

In 2014, Li, Hou, and co-workers synthesized a hydrazide polymer that mimics the ion transport of Gramicidin A. ° This polymer carried phenylalanine side chains, which allowed the polymer to be inserted into a lipid bilayer at low concentrations. Patch clamp experiments showed that this polymer could transport some alkali-metal ions such as Na , K , and also NH4 across the membrane. Patch-current traces up to 15 s showed that the structure was stable within the bilayer. As the NH4 selectivity was higher than that for K, the inner pore was estimated to be smaller than 1 nm. Another field where helical polymers have been used is the Space-Charge-Limited Current (SCLC) hole mobility. In 2015, a discotic polycyclic aromatic... 

Present data indicates that chain growth in both gramicidin S and the tyrocidines commences at the D-phenylalanine residue adjacent to proline and that the first step in the synthesis is the conversion of L-phenylalanine to D-phenyldanine. In the case of the tyrocidines, the synthesis then proceeds in order from the amino to the carboxyl terminus to form a linear decapeptide ending with a thiol ester linked leucine. The peptide then cyclises relatively slowly to the final product. Yamada and Kurahashi showed that the epimerisation of L-phenylalanine in the initial step did not require pyridoxal phosphate or FAD and they suggested that the reaction occurs via the thiol ester enzyme bound form (101), Figure 3.18. 

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