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Industrial production of penicillin:

Penicillin is generated on large scale in a commercially devised fermenter that gives optimum
growth situation to Penicillium chrysogenum for maximum outcome.
Following are the steps included for the production of penicillin:
1) Inoculate 100 ml medium into 500 ml Erlenmeyer flask through spores of Penicillium
chrysogenum strain and incubate at 25oC by keep them on the rotary shaker.
2) Subsequent to 4 days, transfer the content of container to the other container (4 liter capacity)
having 2 liters of medium and incubate 2 days.
3) Transfer the substance to a stainless steel tank (i.e., 800 liter capacity) having 500 liters of
medium. This tank is equipped in such a manner that it could give the optimum situation for
fungal growth.
4) After 3 days, employ the contents for inoculation of around 1,80,000 liter medium kept in
fermenter (i.e., 2,50,000 liter capacity). The later is equipped with automatic devices to optimum
growth circumstances.
5) Filter the content of fermenter subsequent to 6 days incubation.
Filtrate has penicillin. Extract the penicillin into amyl - or butyl acetate. From it transfer
penicillin to aqueous solvent by extracting with phosphate buffer. From a butanol water mix
crystallize the potassium penicillin.

Overall, there are three main and important steps to the biosynthesis of penicillin
G (benzylpenicillin).

The first step is the condensation of three amino acidsL--aminoadipic acid, Lcysteine, L-valine into a tripeptide. Before condensing into the tripeptide, the amino acid Lvaline must undergo epimerization to become D-valine. The condensed tripeptide is named
-(L--aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and
epimerization are both catalyzed by the enzyme -(L--aminoadipyl)-L-cysteine-D-valine
synthetase (ACVS), a nonribosomal peptide synthetase or NRPS.

The second step in the biosynthesis of penicillin G is the oxidative conversion of linear
ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which
is encoded by the gene pcbC. Isopenicillin N is a very weak intermediate, because it does not
show strong antibiotic activity.

The final step is a transamidation by isopenicillin N N-acyltransferase, in which the aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenyl
acetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the
process of obtaining penicillins.

A -lactam (beta-lactam) ring is a four-membered lactam (A lactam is a cyclic amide). It is
named as such because the nitrogen atom is attached to the -carbon atom relative to the
carbonyl. The simplest -lactam possible is 2-azetidinone.

The -lactam ring is part of the core structure of several antibiotic families, the principal ones
being the penicillins, cephalosporins,carbapenems, and monobactams, which are, therefore, also
called -lactam antibiotics. Nearly all of these antibiotics work by inhibiting bacterial cell
wall biosynthesis. This has a lethal effect on bacteria. Bacteria do, however, contain within their
populations, in smaller quantities, bacteria that are resistant against -lactam antibiotics. They do
this by expressing one of many -lactamase genes. More than 1,000 different -lactamase
enzymes have been documented in various species of bacteria. These enzymes vary widely in
their chemical structure and catalytic efficiencies. When bacterial populations have these
resistant subgroups, treatment with -lactam can result in the resistant strain becoming more
prevalent and therefore more virulent.

The first synthetic -lactam was prepared by Hermann Staudinger in 1907 by reaction of
the Schiff base of aniline and benzaldehyde with diphenylketene in a [2+2] cycloaddition:

Up to 1970, most -lactam research was concerned with the penicillin and cephalosporin groups,
but since then, a wide variety of structures have been described.

The Breckpot Synthesis
The synthesis of substituted -lactams from the cyclization of beta amino acid esters using
the Grignard reagent

Due to ring strain, -lactams are more reactive to hydrolysis conditions than are linear amides or
larger lactams. This strain is further increased by fusion to a second ring, as found in most lactam antibiotics. This trend is due to the amide character of the -lactam being reduced by
the aplanarity of the system. The nitrogen atom of an ideal amide is sp2-hybridized due
to resonance, and sp2-hybridized atoms have trigonal planar bond geometry. As a pyramidal bond
geometry is forced upon the nitrogen atom by the ring strain, the resonance of the amide bond is
reduced, and the carbonyl becomes more ketone-like.
Other applications
A new study has suggested that -lactams can undergo ring-opening polymerization to form
amide bonds, to become nylon-3 polymers. The backbones of these polymers are identical to
peptides, which offer them biofunctionality. These nylon-3 polymers can either mimic host
defense peptides or act as signals to stimulate 3T3 stem cell function.
Anti proliferative agents that target tubulin with -lactams in their structure have also been