Prodigiosin

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Prodigiosin
Prodigiosin.svg
Names
IUPAC name
4-Methoxy-5-[(Z)-(5-methyl-4-pentyl-2H-pyrrol-2-ylidene)methyl]-1H,1′H-2,2′-bipyrrole
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
MeSH Prodigiosin
PubChem CID
UNII
  • InChI=1S/C20H25N3O/c1-4-5-6-8-15-11-16(22-14(15)2)12-19-20(24-3)13-18(23-19)17-9-7-10-21-17/h7,9-13,21,23H,4-6,8H2,1-3H3/b16-12+ Yes check.svgY
    Key: SZXDNGVQRDTJSD-FOWTUZBSSA-N Yes check.svgY
  • InChI=1/C20H25N3O/c1-4-5-6-8-15-11-16(22-14(15)2)12-19-20(24-3)13-18(23-19)17-9-7-10-21-17/h7,9-13,21,23H,4-6,8H2,1-3H3/b16-12+
    Key: SZXDNGVQRDTJSD-FOWTUZBSBS
  • CCCCCc3cc(=Cc2[nH]c(c1ccc[nH]1)cc2OC)nc3C
Properties
C20H25N3O
Molar mass 323.440 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Prodigiosin is the red dye produced by many strains of the bacterium Serratia marcescens , [1] [2] as well as other Gram-negative, gamma proteobacteria such as Vibrio psychroerythrus and Hahella chejuensis . It is responsible for the pink tint occasionally found in grime that accumulates on porcelain surfaces such as bathtubs, sinks, and toilet bowls. It is in the prodiginine family of compounds which are produced in some Gram-negative gamma proteobacteria, as well as select Gram-positive Actinobacteria (e.g. Streptomyces coelicolor ). [3] The name prodigiosin is derived from prodigious (i.e. something marvelous).

Contents

Secondary metabolite

Prodigiosin is a secondary metabolite of Serratia marcescens. Because it is easy to detect, it has been used as a model system to study secondary metabolism. Prodigiosin production has long been known to be enhanced by phosphate limitation. In low phosphate conditions, pigmented strains have been shown to grow to a higher density than unpigmented strains. [4]

Religious function

The ability of pigmented strains of Serratia marcescens to grow on bread has led to a possible explanation of Medieval transubstantiation miracles, in which Eucharistic bread is converted into the Body of Christ. Such miracles led to Pope Urban IV instituting the Feast of Corpus Christi in 1264. This followed celebration of a Mass at Bolsena in 1263, led by a Bohemian priest who had doubts concerning transubstantiation. [3] During the Mass, the eucharist appeared to bleed and each time the priest wiped away the blood, more would appear. This event is celebrated in a fresco in the Pontifical Palace in the Vatican City, painted by Raphael: The Mass at Bolsena . [5]

Biological activity

Prodigiosin received renewed attention [3] [6] for its wide range of biological activities, including activities as antimalarial, [7] antifungal, [8] immunosuppressant, [9] and antibiotic agents. [10] It is perhaps best known for its capacity to trigger apoptosis of malignant cancer cells. The exact mechanism of this inhibition is highly complex and not entirely elucidated, but could involve multiple processes, including phosphatase inhibition, copper mediated cleavage of double stranded DNA, or disrupting the pH gradient through transmembrane transport of H+ and Cl- ions. [11] As a result, prodigiosin is a highly promising drug lead, and is currently in preclinical phase study for pancreatic cancer treatment. [12] Prodigiosin has recently been found to have excellent activity against stationary phase Borrelia burgdorferi , the causative agent of Lyme disease. [13]

Production

Biosynthesis

Chemical transformations and gene clusters for prodiginine biosynthetic pathways Prodiginine biosynthesis.jpg
Chemical transformations and gene clusters for prodiginine biosynthetic pathways
Figure 1: Structure of Prodigiosin 1 highlighting the A, B, and C pyrrole rings Prodigiosin 1.png
Figure 1: Structure of Prodigiosin 1 highlighting the A, B, and C pyrrole rings

The biosynthesis of prodigiosin [15] [16] and related analogs, the prodiginines [3] [14] involves the convergent coupling of three pyrrole type rings (labeled A, B, and C in figure 1) from L-proline, L-serine, L-methionine, pyruvate, and 2-octenal. [17]

Ring A is synthesized from L-proline through the nonribosomal peptide synthase (NRPS) pathway (figure 2), wherein the pyrrolidine ring is oxidized, with flavin adenine dinucleotide (FAD+) as the coenzyme to yield pyrrole ring A. In the first step, proline is attached to a peptidyl carrier protein (PCP) called pigG by the action of the enzyme pigI and then the enzyme pigA performs the oxidation.

Prodigiosin Ring A.png

Ring A is then expanded via the polyketide synthase pathway to incorporate L-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 keto-synthase (KS) domain, followed by transfer to malonyl-ACP via decarboxylative Claisen condensation catalysed by the enzyme pigJ. This fragment is then able to react with the masked carbanion formed from the pyridoxal phosphate (PLP) mediated decarboxylation of L-serine, which cyclizes in a dehydration reaction to yield the second pyrrole ring. This intermediate is then modified by oxidation of the primary alcohol to the aldehyde, catalysed by pigM, and methylation (which incorporates a methyl group from L-methionine onto the alcohol at the 6-position) catalysed by pigF and pigN. This yields the core A-B ring structure ready for further transformations, including to the tambjamines [18] as well as the prodiginines.

Prodigiosin Ring B.png

Ring C is formed from the thiamine pyrophosphate (TPP) mediated decarboxylative addition of pyruvate to 2-octenal, catalysed by pigD. PigE then converts the intermediate to an amine (using an amino-acid and PLP) ready for intramolecular condensation. PigB oxidises the resulting ring using oxygen and FAD+, yielding the pyrrole.

Ring C.png

Finally, the two pieces are combined by pigC and its cofactor adenosine triphosphate (ATP) in a dehydration reaction which establishes a conjugated system across all three rings and completes the synthesis of prodigiosin.

Convergent synthesis.png

Laboratory

Details of the first total synthesis of prodigiosin were published in 1962, confirming the chemical structure. As with the biosynthesis, the key intermediate was the A-B aldehyde shown in Figure 5. [19] This aldehyde has subsequently been prepared by other methods and used to make prodigiosin and related natural products. [16]

Uses

Potential pharmaceutical uses of prodigiosin, or its use as a dyestuff, have led to studies of its production from Serratia marcescens, possibly after genetic modification. [20]

See also

Related Research Articles

Pyrrole is a heterocyclic, aromatic, organic compound, a five-membered ring with the formula C4H4NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3. Porphobilinogen, a trisubstituted pyrrole, is the biosynthetic precursor to many natural products such as heme.

<i>Serratia marcescens</i> Species of bacterium

Serratia marcescens is a species of rod-shaped, Gram-negative bacteria in the family Yersiniaceae. It is a facultative anaerobe and an opportunistic pathogen in humans. It was discovered in 1819 by Bartolomeo Bizio in Padua, Italy. S. marcescens is commonly involved in hospital-acquired infections (HAIs), also called nosocomial infections, particularly catheter-associated bacteremia, urinary tract infections, and wound infections, and is responsible for 1.4% of HAI cases in the United States. It is commonly found in the respiratory and urinary tracts of hospitalized adults and in the gastrointestinal systems of children.

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

Mycolic acids are long fatty acids found in the cell walls of Mycobacteriales taxon, a group of bacteria that includes Mycobacterium tuberculosis, the causative agent of the disease tuberculosis. They form the major component of the cell wall of many Mycobacteriales species. Despite their name, mycolic acids have no biological link to fungi; the name arises from the filamentous appearance their presence gives Mycobacteriales under high magnification. The presence of mycolic acids in the cell wall also gives Mycobacteriales a distinct gross morphological trait known as "cording". Mycolic acids were first isolated by Stodola et al. in 1938 from an extract of M. tuberculosis.

<span class="mw-page-title-main">Formylation</span>

Formylation refers to any chemical processes in which a compound is functionalized with a formyl group (-CH=O). In organic chemistry, the term is most commonly used with regards to aromatic compounds. In biochemistry the reaction is catalysed by enzymes such as formyltransferases.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

Purine metabolism refers to the metabolic pathways to synthesize and break down purines that are present in many organisms.

<span class="mw-page-title-main">1-Pyrroline-5-carboxylic acid</span> Chemical compound

1-Pyrroline-5-carboxylic acid is a cyclic imino acid. Its conjugate base and anion is 1-pyrroline-5-carboxylate (P5C). In solution, P5C is in spontaneous equilibrium with glutamate-5-semialdhyde (GSA).

<span class="mw-page-title-main">Transsulfuration pathway</span>

The transsulfuration pathway is a metabolic pathway involving the interconversion of cysteine and homocysteine through the intermediate cystathionine. Two transsulfurylation pathways are known: the forward and the reverse.

The enzyme ectoine synthase (EC ) catalyzes the chemical reaction

In enzymology, a carbamate kinase (EC 2.7.2.2) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Aldehyde dehydrogenase 18 family, member A1</span> Protein-coding gene in the species Homo sapiens

Delta-1-pyrroline-5-carboxylate synthetase (P5CS) is an enzyme that in humans is encoded by the ALDH18A1 gene. This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. As reported by Bruno Reversade and colleagues, ALDH18A1 deficiency or dominant-negative mutations in P5CS in humans causes a progeroid disease known as De Barsy Syndrome.

<span class="mw-page-title-main">Cobalamin biosynthesis</span>

Cobalamin biosynthesis is the process by which bacteria and archea make cobalamin, vitamin B12. Many steps are involved in converting aminolevulinic acid via uroporphyrinogen III and adenosylcobyric acid to the final forms in which it is used by enzymes in both the producing organisms and other species, including humans who acquire it through their diet.

Cysteate synthase is an enzyme with systematic name sulfite:O-phospho-L-serine sulfotransferase . This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Fumitremorgin</span>

Fumitremorgins are tremorogenic metabolites of Aspergillus and Penicillium, that belong to a class of naturally occurring 2,5-diketopiperazines.

<span class="mw-page-title-main">Tambjamine</span> Chemical compound

Tambjamines are a group of natural products that are structurally related to the prodiginines. They are enamine derivatives of 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC).

<span class="mw-page-title-main">Pentabromopseudilin</span> Chemical compound

Pentabromopseudilin, the first reported marine microbial antibiotic, is a bioactive natural product that contains a highly halogenated 2-arrylpyrrole moiety. Pentabromopseudilin (PBP) is a unique hybrid bromophenol-bromopyrrole compound that is made up of over 70% bromine atoms, contributing to its potent bioactivity. PBP was first isolated from Pseudomonas bromoutilis, and has since been found to be produced by other marine microbes, including Alteromonas luteoviolaceus, Chromobacteria, and Pseudoalteromonas spp.

<span class="mw-page-title-main">Chlorophyllide</span> Chemical compound

Chlorophyllide a and Chlorophyllide b are the biosynthetic precursors of chlorophyll a and chlorophyll b respectively. Their propionic acid groups are converted to phytyl esters by the enzyme chlorophyll synthase in the final step of the pathway. Thus the main interest in these chemical compounds has been in the study of chlorophyll biosynthesis in plants, algae and cyanobacteria. Chlorophyllide a is also an intermediate in the biosynthesis of bacteriochlorophylls.

<span class="mw-page-title-main">Undecylprodigiosin</span> Chemical compound

Undecylprodigiosin is an alkaloid produced by some Actinomycetes bacteria. It is a member of the prodiginines group of natural products and has been investigated for potential antimalarial activity.

<span class="mw-page-title-main">Prodiginines</span>

The prodiginines are a family of red tripyrrole dyestuffs produced by Gammaproteobacteria as well as some Actinomycetota. The group is named after prodigiosin (prodiginine) and is biosynthesized through a common set of enzymes. They are interesting due to their history and their varied biological activity.

References

  1. ↑ Bennett JW, Bentley R (2000). "Seeing red: The story of prodigiosin". Adv Appl Microbiol. Advances in Applied Microbiology. 47: 1–32. doi:10.1016/S0065-2164(00)47000-0. ISBN   9780120026470. PMID   12876793.
  2. ↑ Yu, Victor L. (1979). "Serratia marcescens — Historical Perspective and Clinical Review". New England Journal of Medicine. 300 (16): 887–893. doi:10.1056/NEJM197904193001604. PMID   370597.
  3. 1 2 3 4 Williamson NR, Fineran PC, Gristwood T, Leeper FJ, Salmond GP (2006). "The biosynthesis and regulation of bacterial prodiginines". Nature Reviews Microbiology. 4 (12): 887–899. doi:10.1038/nrmicro1531. PMID   17109029. S2CID   11649828.
  4. ↑ M. Todd-Guay and P.H. Demchick. 1995. Role of prodigiosin in phosphate-starved Serratia marcescens. Abstract of the Annual Meeting, American Society for Microbiology.
  5. ↑ "The Mass at Bolsena by Raphael". Vatican Museums. Retrieved 2017-08-18.
  6. ↑ Williamson NR, Fineran PC, Gristwood T, Chawrai SR, Leeper FJ, Salmond GP (2007). "Anticancer and immunosuppressive properties of bacterial prodiginines". Future Microbiol. 2 (6): 605–618. doi:10.2217/17460913.2.6.605. PMID   18041902.
  7. ↑ Castro, A. J. (1967). "Antimalarial Activity of Prodigiosin". Nature. 213 (5079): 903–904. Bibcode:1967Natur.213..903C. doi:10.1038/213903a0. PMID   6030049. S2CID   4221849.
  8. ↑ Berg, G. Diversity of antifungal and plant-associated Serratia plymuthica strains. J. Appl. Microbiol. 88, 952–960 (2000).
  9. ↑ Magae, J., Miller, M. W., Nagai, K. & Shearer, G. M. Effect of metacycloprodigiosin, an inhibitor of killer T cells on murine skin and heart transplants. J. Antibiot. (Tokyo) 49, 86–90 (1996).
  10. ↑ Kataoka, T.; et al. (1995). "Prodigiosin 25-C uncouples vacuolar type H+-ATPase, inhibits vacuolar acidification and affects glycoprotein processing". FEBS Lett. 359 (1): 53–59. doi: 10.1016/0014-5793(94)01446-8 . PMID   7851530. S2CID   30504320.
  11. ↑ Rastogi, S.; et al. (2013). "Synthetic prodigiosenes and the influence of C-ring substitution on DNA cleavage, transmembrane chloride transport and basicity". Org. Biomol. Chem. 11 (23): 3834–3845. doi:10.1039/c3ob40477c. PMID   23640568.
  12. ↑ Perez-Tomas, R.; Vinas, M. (2010). "New Insights on the Antitumoral Properties of Prodiginines". Curr. Med. Chem. 17 (21): 2222–2231. doi:10.2174/092986710791331103. PMID   20459382.
  13. ↑ Feng, Jie; Shi, Wanliang; Zhang, Shuo; Zhang, Ying (3 June 2015). "Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection". Emerging Microbes & Infections. 4 (5): e31–. doi:10.1038/emi.2015.31. PMC   5176177 . PMID   26954881.
  14. 1 2 Sakai-Kawada, Francis E.; Ip, Courtney G.; Hagiwara, Kehau A.; Awaya, Jonathan D. (2019). "Biosynthesis and Bioactivity of Prodiginine Analogs in Marine Bacteria, Pseudoalteromonas: A Mini Review". Frontiers in Microbiology. 10: 1715. doi: 10.3389/fmicb.2019.01715 . PMC   6667630 . PMID   31396200.
  15. ↑ Walsh, Christopher T.; Garneau-Tsodikova, Sylvie; Howard-Jones, Annaleise R. (2006). "Biological formation of pyrroles: Nature's logic and enzymatic machinery". Natural Product Reports. 23 (4): 517–31. doi:10.1039/B605245M. PMID   16874387.
  16. 1 2 Hu, Dennis X.; Withall, David M.; Challis, Gregory L.; Thomson, Regan J. (2016). "Structure, Chemical Synthesis, and Biosynthesis of Prodiginine Natural Products". Chemical Reviews. 116 (14): 7818–7853. doi:10.1021/acs.chemrev.6b00024. PMC   5555159 . PMID   27314508.
  17. ↑ R. Caspi (2014-08-14). "Pathway: prodigiosin biosynthesis". MetaCyc Metabolic Pathway Database. Retrieved 2021-04-01.
  18. ↑ Brass, Hannah U. C.; Klein, Andreas S.; Nyholt, Silke; Classen, Thomas; Pietruszka, Jörg (2019). "Condensing Enzymes from Pseudoalteromonadaceae for Prodiginine Synthesis". Advanced Synthesis & Catalysis. doi: 10.1002/adsc.201900183 .
  19. ↑ Rapoport, Henry.; Willson, Clyde D. (1962). "The Preparation and Properties of Some Methoxypyrroles". Journal of the American Chemical Society. 84 (4): 630–635. doi:10.1021/ja00863a025.
  20. ↑ Yip, Chee-Hoo; Yarkoni, Orr; Ajioka, James; Wan, Kiew-Lian; Nathan, Sheila (2019). "Recent advancements in high-level synthesis of the promising clinical drug, prodigiosin". Applied Microbiology and Biotechnology. 103 (4): 1667–1680. doi:10.1007/s00253-018-09611-z. PMID   30637495. S2CID   58004883.
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