Editing Pyrrole (section)

==Biosynthesis==
The biosynthesis of pyrrole rings begins with [[aminolevulinic acid]] (ALA), which is synthesized from [[glycine]] and [[succinyl-CoA]]. ALA dehydratase catalyzes the condensation of two ALA molecules via a [[Knorr pyrrole synthesis|Knorr-type]] ring synthesis to form [[porphobilinogen]] (PBG). This later reacts to form, for example, the macrocycles [[heme]] and [[chlorophyll]].<ref>{{cite journal|last1=Walsh|first1=Christopher T.|last2=Garneau-Tsodikova |first2=Sylvie|author2-link= Sylvie Garneau-Tsodikova |last3=Howard-Jones |first3=Annaleise R. |title=Biological formation of pyrroles: Nature's logic and enzymatic machinery|journal=Natural Product Reports|volume=23|issue=4|pages=517–531|doi=10.1039/b605245m|year=2006|pmid=16874387}}</ref> 
 
[[File:Porphobilinogen Synthesis.jpg|center|class=skin-invert-image|Mechanism of biosynthesis of porphobilinogen]].

[[Proline]] is [[Biosynthesis|biosynthetically]] derived from the amino acid <small>L</small>-[[glutamate]].  [[Glutamate-5-semialdehyde]] is first formed by [[glutamate 5-kinase]] (ATP-dependent) and [[glutamate-5-semialdehyde dehydrogenase]] (which requires NADH or NADPH). This can then either spontaneously cyclize to form [[1-pyrroline-5-carboxylic acid]], which is reduced to proline by [[pyrroline-5-carboxylate reductase]] (using NADH or NADPH), or turned into [[ornithine]] by [[ornithine aminotransferase]], followed by cyclisation by [[ornithine cyclodeaminase]] to form proline.<ref>{{Lehninger3rd}}.</ref>

[[File:Betain-Proline.png|thumb|left|260px|class=skin-invert-image|[[Zwitterion]]ic structure of both proline enantiomers: (''S'')-proline (left) and (''R'')-proline]]

Proline can be used as precursor of aromatic pyrroles in secondary natural products, as in prodigiosins. 
[[File:Prodigiosin 1.png|thumb|left|class=skin-invert-image|Figure 1: Structure of Prodigiosin 1 highlighting the A, B, and C pyrrole rings]]
The biosynthesis of Prodigiosin<ref>{{cite journal | last1 = Walsh | first1 = C. T. | last2 = Garneau-Tsodikova | first2 = S. | last3 = Howard-Jones | first3 = A. R. | year = 2006 | title = Biological formation of pyrroles: Nature's logic and enzymatic machinery | journal = Nat. Prod. Rep. | volume = 23 | issue = 4 | pages = 517–531 | doi = 10.1039/b605245m | pmid = 16874387 }}</ref><ref name=Hu>{{cite journal | doi = 10.1021/acs.chemrev.6b00024 | volume=116 | title=Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products | year=2016 | journal=Chemical Reviews | pages=7818–7853 | last1 = Hu | first1 = Dennis X. | issue=14 | pmid=27314508 | pmc=5555159}}</ref> involves the convergent coupling of three pyrrole type rings (labeled A, B, and C in figure 1) from <small>L</small>-proline, <small>L</small>-serine, <small>L</small>-methionine,  pyruvate, and 2-octenal.

Ring A is synthesized from <small>L</small>-proline through the nonribosomal peptide synthase (NRPS) pathway (figure 2), wherein the pyrrolidine ring of proline is oxidized twice through FAD<sup>+</sup> to yield pyrrole ring A.

[[File:Prodigiosin Ring A.png|class=skin-invert-image|Figure 2: biosynthesis of pyrrole ring A]]

Ring A is then expanded via the polyketide synthase pathway to incorporate <small>L</small>-serine into ring B (figure 3). Ring A fragment is transferred from the peptidyl carrier protein  (PCP) to the Acyl Carrier Protein (ACP) by a KS domain, followed by transfer to malonyl-ACP via decarboxylative Claisen condensation. This fragment is then able to react with the masked carbanion formed from the PLP mediated decarboxylation of <small>L</small>-serine, which cyclizes in a dehydration reaction to yield the second pyrrole ring. This intermediate is then modified by methylation (which incorporates a methyl group from <small>L</small>-methionine onto the alcohol at the 6 position) and oxidation of the primary alcohol to the aldehyde to yield the core A–B ring structures.

[[File:Prodigiosin Ring B.png|class=skin-invert-image|Biosynthesis of pyrrole ring B]]