Editing Penicillin (section)

=== Biosynthesis ===
[[File:Penicillin-biosynthesis.png|class=skin-invert-image|thumb|upright=1.2|Penicillin G biosynthesis]]

The biosynthetic gene cluster for penicillin was first cloned and sequenced in 1990.<ref name="l151">{{cite journal | vauthors = Díez B, Gutiérrez S, Barredo JL, van Solingen P, van der Voort LH, Martín JF | title = The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes | journal = The Journal of Biological Chemistry | volume = 265 | issue = 27 | pages = 16358–16365 | date = September 1990 | pmid = 2129535 | doi = 10.1016/S0021-9258(17)46231-4 | doi-access = free }}</ref> Overall, there are three main and important steps to the biosynthesis of [[penicillin G]] (benzylpenicillin).

* The first step is the condensation of three amino acids—<small>L</small>-α-aminoadipic acid, <small>L</small>-cysteine, <small>L</small>-valine into a [[tripeptide]].<ref name ="Regulation">{{cite book| title = Molecular Biotechnology of Fungal beta-Lactam Antibiotics and Related Peptide Synthetases| volume = 88| veditors = Brakhage AA | vauthors = Al-Abdallah Q, Brakhage AA, Gehrke A, Plattner H, Sprote P, Tuncher A| chapter = Regulation of Penicillin Biosynthesis in Filamentous Fungi| year = 2004| issue = 88| pages = 45–90| doi = 10.1007/b99257| pmid = 15719552| isbn = 978-3-540-22032-9| series = Advances in Biochemical Engineering/Biotechnology}}</ref><ref name=Molecular>{{cite journal | vauthors = Brakhage AA | title = Molecular regulation of beta-lactam biosynthesis in filamentous fungi | journal = Microbiology and Molecular Biology Reviews | volume = 62 | issue = 3 | pages = 547–85 | date = September 1998 | pmid = 9729600 | pmc = 98925 | doi = 10.1128/MMBR.62.3.547-585.1998 }}</ref><ref>{{cite journal | vauthors = Schofield CJ, Baldwin JE, Byford MF, Clifton I, Hajdu J, Hensgens C, Roach P | title = Proteins of the penicillin biosynthesis pathway | journal = Current Opinion in Structural Biology | volume = 7 | issue = 6 | pages = 857–64 | date = December 1997 | pmid = 9434907 | doi = 10.1016/s0959-440x(97)80158-3 }}</ref> Before condensing into the tripeptide, the amino acid <small>L</small>-valine must undergo epimerization to become <small>D</small>-valine.<ref name=Fern>{{cite journal | vauthors = Martín JF, Gutiérrez S, Fernández FJ, Velasco J, Fierro F, Marcos AT, Kosalkova K | title = Expression of genes and processing of enzymes for the biosynthesis of penicillins and cephalosporins | journal = Antonie van Leeuwenhoek | volume = 65 | issue = 3 | pages = 227–43 | date = September 1994 | pmid = 7847890 | doi = 10.1007/BF00871951 | s2cid = 25327312 }}</ref><ref>{{cite journal | vauthors = Baker WL, Lonergan GT | title = Chemistry of some fluorescamine–amine derivatives with relevance to the biosynthesis of benzylpenicillin by fermentation. | journal = Journal of Chemical Technology & Biotechnology | date = December 2002 | volume = 77 | issue = 12 | pages = 1283–88 | doi = 10.1002/jctb.706 | bibcode = 2002JCTB...77.1283B }}</ref> The condensed tripeptide is named δ-(<small>L</small>-α-aminoadipyl)-<small>L</small>-cysteine-<small>D</small>-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme δ-(<small>L</small>-α-aminoadipyl)-<small>L</small>-cysteine-<small>D</small>-valine synthetase (ACVS), a [[nonribosomal peptide]] synthetase or NRPS.
* The second step in the biosynthesis of penicillin G is the [[Redox|oxidative]] conversion of linear ACV into the [[Bicyclic molecule|bicyclic]] intermediate isopenicillin N by [[isopenicillin N synthase]] (IPNS), which is encoded by the gene ''pcbC''.<ref name ="Regulation" /><ref name=Molecular /> Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity.<ref name=Fern />
* The final step is a [[transamidation]] by [[isopenicillin N N-acyltransferase]], in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a [[Phenylacetic acid|phenylacetyl]] side-chain. This reaction is encoded by the gene ''penDE'', which is unique in the process of obtaining penicillins.<ref name ="Regulation" />