The inhibition by bacitracin of the en- Bacitracin is an antibiotic produced by strains of Bacillus licheniformis. It is a mixture of closely related compounds, the main component of which (bacitracin A) is a cyclic polypeptide with a peptide side chain ( Fig. 1) (1-3). An unusual feature of the structure is the occurrence of a thiazoline ring formed between the L-cysteine and L-isoleucine residues at the N-terminal end of the acylic peptide side-chain. The free amino group of iisoleucine at the N-terminal end is adjacent to the thiazoline ring and is essential for antimicrobial activity. The transformation of bacitracin A to bacitracin F (in which the amino group is replaced by a carbonyl group) results in total loss of antimicrobial activity. A metal ion may be essential for the antimicrobial activity of bacitracin (4-1 1). The antimicrobial activity is stimulated by various metal ions and inhibited by metal-chelating agents, such as EDTA. Spectroscopic evidence for the interaction of bacitracin with metal ions has been obtained. The chelation may involve both the nitrogen of the thiazoline ring and the adjacent free amino-group in isoleucine; this chelation could assist in stabilizing the thiazoline ring, thus hindering the deamination to bacitracin F (10). It has been further postulated that in the zinc-bacitracin A complex, the zinc also coordinates through the imidazole of the histidine residue and the peptide nitrogen of the histidine residue, thus forming a oneto-one complex with bacitracin (10).Various biochemical lesions induced by bacitracin have been reported (9). Several effects, such as inhibition of induced enzyme synthesis and stimulation of efflux of K+ ions, could be ascribed to alterations in cell-membrane function. The antibiotic also inhibits incorporation of ['4C]aminoacids into cell walls and induces the accumulation of uridine-nucleotide precursors of the wall under conditions in which incorporation of amino acids into protein is unaffected (12-15). However, since bacitracin affects protoplasts of bacteria, its action is not limited to effects on cell walls. The precise site of action in cell wall synthesis has been defined as inhibition of the dephosphorylation of C55-isoprenyl pyrophosphate. This reaction is essential for regeneration of the lipid carrier required for the cyclic synthesis of peptidoglycan (16, 17). In the present paper, data are presented which suggest that bacitracin acts by forming a complex with C55-isoprenyl pyrophosphate (a component of the cell membrane) and divalent cations. The metal ion may serve as a bridge between the antibiotic and the substrate. MATERIALS AND METHODSThe C55-isoprenyl pyrophosphatase used was that present in membranes of Streptococcus fecalis. The membranes were prepared and washed with EDTA and 2 M LiCl as described previously (through step 2 of the procedure) (Staudenbauer, W. L., and J. L., Strominger, J. Biol. Chem., submitted). The residual LiCl was removed by washing with water and then dialysis against water. Finally, the memb...
Evidence from mass, nuclear-magnetic-resonance and infrared spectrometry and from gas-liquid and thin-layer chromatography is presented in favour of the presence of cis-trans-decaprenol, -undecaprenol and -dodecaprenol in the mixture of polyprenols (2.6mg./g.) isolated from leaf tissue of Ficus elastica. The trivial names ficaprenol-10, -11 and -12 are proposed. Nuclear-magnetic-resonance studies showed that each of these prenols contains three trans internal isoprene residues and a cis ;OH-terminal' isoprene residue. Ficaprenol-11 is the major component of the mixture. Chromatographic evidence suggests the presence also of small amounts of ficaprenol-9 and -13. The precise position of the three trans internal isoprene residues was not determined but it is suggested that these are adjacent to the omega-terminal isoprene residue and that the ficaprenols are formed from all-trans-geranylgeranyl pyrophosphate. It is also suggested that ficaprenol-10, -11, -12 and -13 are probably the same compounds as castaprenol-10, -11, -12 and -13.
Orally administered dihomo-gamma-linolenic acid (DHLA) is well absorbed in man; it appears in blood after ca. 4 hr first as triglyceride ester and later as phospholipid. After sustained-dosing, DHLA penetrated membrane pools and all phospholipid components but, depending on the dosage, reached a metabolic equilibrium in 4-16 days. Intact platelets do not accumulate arachidonate following DHLA administration, and species differences occur in the capacity of animals to metabolize DHLA to arachidonic acid (AA). The rat appears to be unusual in having a very active hepatic delta5-desaturase enzyme system. Potentially antithrombotic changes in platelet function which followed the administration of DHLA to man were accompanied by a significant increase in the capacity of platelets to synthesize PGE1. Concomitant increases in PGE2 synthesis do not apparently result from an increased production of AA and suggest that DHLA, or a DHLA metabolite, interferes with the metabolism of AA. Effects on thromboxane and prostacyclin synthesis are being studied.
SummaryThe effects of orally ingested dihomo---linolenic acid (DHLA), the natural biosynthetic precursor of prostaglandin El (PGE,), were assessed in human volunteers. Single doses of DHLA (0 1-2g) increased the proportion of DHLA relative to arachidonic acid in plasma and platelets and also increased the ex-vivo capacity of platelets to produce PGE, and PGE2. More pronounced effects were observed during sustained treatment (five days to four weeks) when DHLA also accumulated in red cell membranes. These biochemical changes were accompanied by potentially antithrombotic changes in haemostatic function. The most common effect, which was consistently detected after 0 1-g single doses of DHLA or its methyl ester, was a decrease in plasma heparin-neutralising activity. Inhibition of platelet aggregation induced by adenosine diphosphate was also detected, though this was generally less pronounced. Sustained treatment in one subject also produced definite inhibition of ristocetininduced platelet aggregation. There was only one possible adverse effect-a transient cough in a subject with a history of asthma.
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