Cephalosporium acremonium

In 1945 it was noted that a strain of Cephalosporium acremonium i oAu ced antibiotic material that was active against gram-negative as weU as gram-positive... 

Fig. 1. Biosynthesis of cephalosporins and cephamycins. a, Cephalosporium acremonium, b, Penicillium chjsogenum, c, Streptomjces clavuligerus-, d, Streptomjces lipmanir, e, Streptomjces wadajamensis, REX is a ring expansion en2yme (deacetoxycephalosporin C synthethase).

Fermentation. The commercial P-lactam antibiotics which act as starting material for all of the cephalosporins ate produced by submerged fermentation. The organisms used for the commercial production of the penicillins and cephalosporins ate mutants of PenicU/in chTysogenum and Cephalosporium acremonium respectively (3,153,154). Both ate tme fungi (eucaryotes). In contrast, the cephamycins ate produced by certain species of procaryotic Streptomyces including Streptomyces clavuligerus and Streptomyces lipmanii (21,103). 

Cephalosporin Cephalosporium acremonium Broad spectrum Wall synthesis... 

The ancestral strain of Acremonium chrysogenum (at that time called Cephalosporium acremonium) was isolated on the Sardinian coast in 1945 following an observation that the local sewage outlet into the sea cleared at a quite remarkable rate. Advances were slow because the activity was associated with a number of different types of compound. Cephalosporin C was first isolated in 1952, but it was a further decade before clinically usefiil semisynthetic cephalosporins became available. 

Also at Oxford, Abraham and Newton discovered the first cephalosporin, cephalosporin C, as a product of Acremonium chrysogenum (Cephalosporium acremonium).17 This new, sulfur-containing antibiotic was also a (5-lactam but the fused, sulfur-containing ring is a six-membered dihydrothiazine. 

Cephalosporins display an antibiotic mechanism of action identical to that of the penicillins. Cephalosporin C (Figure 1.14) is the prototypic natural cephalosporin and is produced by the fungus Cephalosporium acremonium. Most other members of this family are semi-synthetic derivatives of cephalosporin C. Chemical modification normally targets side-chains at position 3 (the acetoxymethyl group) or 7 (derived from D-a-aminoadipic acid). 

Cephalosporins are important bactericidal broad spectrum (3-lactam antibiotics used for the treatment of septicaemia, pneumonia, meningitis, urinary tract infections, peritonitis and biliary tract infections. They are obtained from fungus Cephalosporium acremonium and are chemically related to penicillin. It consists of beta lactam ring fused to a dihydrothiazine ring. 

Part of the biogenesis of cephalosporins was confirmed by isolating 13C-labeled compounds [1014]. Adding [2-13C]-acetate to cultures of Cephalosporium acremonium yielded an antibiotic labeled at C-l 1, -12, -13, -14 and -19 (marked with asterisks in the formula) [l-13C]-acetate, on the other hand, yielded a compound labeled at positions 10, 15 and 18 (symbolized by in the formula). 

Deacetoxy/deacetylcephalosporin C synthase (DAOC/DACS), the enzyme isolated from Cephalosporium acremonium catalysing587 the ring expansion of penicillin N, 473, to deacetoxycephalosporin (DAOC), 474, and the hydroxylation of 474 to deacetylcephalosporin C(DAC), 475, which in vivo is acetylated by a different enzyme to give cephalosporin C, 476 (equation 284), converts also the unnatural substrate exomethylene cephalosporin C, 477a, directly to DAC, 475 (equation 285). 

Zhang H-W, Huang W-Y, Song Y-C, Chen J-R, Tan R-X (2005) Four 6//-Dibenzo[b,rf] pyran-6-one Derivatives Produced by the Endophyte Cephalosporium acremonium IFB-E007. Helv Chim Acta 88 2861... 

Cephalosporin C (Figure 7.37) is produced commercially by fermentation using cultures of a high-yielding strain of Acremonium chrysogenum (formerly Cephalosporium acremonium). Initial studies of the antibiotic compounds synthesized by C. acremonium identified penicillin N (originally called cephalosporin N) as the major component, with small amounts of cephalosporin C. In contrast to the penicillins, cephalosporin C was stable under acidic conditions and also was not attacked by penicillinase ((5-lactamase). Antibacterial activity was rather low, however, and the antibiotic was poorly absorbed after oral administration. However, the structure offered considerable scope for side-chain modifications, more so than with the penicillins since it has two side-chains, and this has led to a wide variety of cephalosporin drugs, many of which are currently in clinical use. As with the penicillins, removal of the amide... 

H Shirafuji, Y Fujisawa, M Kida, T Kanzaki, M Yoneda. Accumulation of tripeptide derivatives by mutants of Cephalosporium acremonium. Agric Biol Chem 43 155-160, 1979. 

RM Adlington, JE Baldwin, M Lopez-Nieto, JA Murphy, N Patel. A study of the biosynthesis of the tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine in a beta-lactam-negative mutant of Cephalosporium acremonium. Biochem J 213 573-576, 1983. 

JE Baldwin, JW Bird, RA Fields, NM O Callaghan, CJ Schofield. Isolation and partial characterization of ACV synthetase from Cephalosporium acremonium and Streptomyces clavuligerus. J Antibiot 43 1055-1057, 1990. 

J Zhang, AL Demain. Purification from Cephalosporium acremonium of the initial enzyme unique to the biosynthesis of penicillins and cephalosporins. Biochem Biophys Res Commun 169 1145-1152, 1990. 

JE Baldwin, C-Y Shiau, MF Byford, CJ Schofield. Substrate specificity of delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine formed by ACV synthetase from Cephalosporium acremonium. demonstration of the structure of several unnatural tripeptide products. Biochem J 301 367-372, 1994. 

LH Malmberg, WS Hu. Identification of rate-limiting steps in cephalosporin C biosynthesis in Cephalosporium acremonium. a theoretical analysis. Appl Microbiol Biotechnol 38 122-128, 1992. 

The name of Cephalosporium acremonium has been changed to Acremonium chrysogenum however, Cephalosporium acremonium is used here for historic continuity, since most of the literature contains this name. 

JE Baldwin, J Gagnon, H Ting. N-terminal amino acid sequence and some properties of isopenicillin-N synthetase from Cephalosporium acremonium. FEBS Lett 188 253-256, 1985. 

SM Samson, R Belagaje, DT Blankenship, JL Chapman, D Perry, PL Skatrud, RM VanFrank, EP Abraham, JE Baldwin, SW Queener, TD Ingolia. Isolation, sequence determination and expression in Escherichia coli of the isopenicillin N synthetase gene from Cephalosporium acremonium. Nature 318 191-194, 1985. 

M Kohsaka, AL Demain. Conversion of penicillin N to cephalosporin(s) by cell-free extracts of Cephalosporium acremonium. Biochem Biophys Res Commun 70 465-473, 1976. 

J Kupka, YQ Shen, S Wolfe, AL Demain. Studies on the ring-cyclization and ring-expansion enzymes of (3-lactam biosynthesis in Cephalosporium acremonium. Can J Microbiol 29 488-496, 1983. 

A Scheidegger, MT Kuenzl, JNuesch. Partial purification and catalytic properties of a bifunctional enzyme in the biosynthetic pathway of (3-lactams in Cephalosporium acremonium. J Antibiot 37 522-531, 1984. 

JE Dotzlaf, WK Yeh. Copurification and characterization of deacetoxycephalosporin C synthetase/hydroxylase from Cephalosporium acremonium. J Bacteriol 169 1611-1618, 1987. 

Y Fujisawa, T Kanzaki. Role of acetyl CoA deacetylcephalosporin C acetyltransfer-ase in cephalosporin C biosynthesis by Cephalosporium acremonium. Agric Biol Chem 39 2043-2048, 1975. 

A Scheidegger, A Gutzwiller, M Kueenzi, A Fiechter, J Nuesch. Investigation of acetyl-CoA deacetylcephalosporin C O-acetyltransferae of Cephalosporium acremonium. J Biotechnol 3 109-117, 1985. 

S Gutierrez, J Velasco, FJ Fernandez, JF Martin. The cefG gene of Cephalosporium acremonium is linked to the ce/EF gene and encodes a deacetylcephalosporin C acetyltransferase closely related to homoserine O-acetyltransferase. J Bacteriol 174 3056-3064, 1992. 

L Mathison, C Soliday, T Stepan, T Aldrich, J Rambosek. Cloning, characterization, and use in strain improvement of the Cephalosporium acremonium gene cefG encoding acetyl transferase. Curr Genet 23 33 41, 1993. 

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