Petrobactin

Petrobactin
Names
Preferred IUPAC name
4-[4-[3-[(3,4-dihydroxybenzoyl)amino]propylamino]butylamino]-2-[2-[4-[3-[(3,4-dihydroxybenzoyl)amino]propylamino]butylamino]-2-oxoethyl]-2-hydroxy-4-oxobutanoic acid
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
KEGG
  • InChI=1S/C34H50N6O11/c41-25-9-7-23(19-27(25)43)31(47)39-17-5-13-35-11-1-3-15-37-29(45)21-34(51,33(49)50)22-30(46)38-16-4-2-12-36-14-6-18-40-32(48)24-8-10-26(42)28(44)20-24/h7-10,19-20,35-36,41-44,51H,1-6,11-18,21-22H2,(H,37,45)(H,38,46)(H,39,47)(H,40,48)(H,49,50)
    Key: GKIMOVAPSAVJHZ-UHFFFAOYSA-N
  • H+: InChI=1S/C34H50N6O11/c41-25-9-7-23(19-27(25)43)31(47)39-15-3-1-11-35-13-5-17-37-29(45)21-34(51,33(49)50)22-30(46)38-18-6-14-36-12-2-4-16-40-32(48)24-8-10-26(42)28(44)20-24/h7-10,19-20,35-36,41-44,51H,1-6,11-18,21-22H2,(H,37,45)(H,38,46)(H,39,47)(H,40,48)(H,49,50)/p+1
    Key: SESZZOOISCLDTE-UHFFFAOYSA-O
  • C1=CC(=C(C=C1C(=O)NCCCNCCCCNC(=O)CC(CC(=O)NCCCCNCCCNC(=O)C2=CC(=C(C=C2)O)O)(C(=O)O)O)O)O
  • H+: C(=O)([O-])C(CC(=O)NCCC[NH2+]CCCCNC(C1=CC=C(C(=C1)O)O)=O)(CC(=O)NCCC[NH2+]CCCCNC(C2=CC=C(C(=C2)O)O)=O)O
Properties
C34H50N6O11
Molar mass 718.79 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Petrobactin is a metal-binding natural product used for iron acquisition by Bacillus anthracis, the pathogen that causes anthrax, as well as in other bacterial species such as Marinobacter hydrocarbonoclasticus, and Alteromonas macleodii. It is of the bis-catechol (3,4-dihydroxybenzoyl) class of such siderophores.[non-primary source needed] As with others in this class, petrobactin serves as a highly specific iron(III) transport ligand, and contributes to marine microbial uptake of environmental iron.[non-primary source needed]

The iron-chelated petrobactin complex readily undergoes an uncatalysed, light-mediated decarboxylation—a photo-oxidation—of its metal-associated secondary carboxylic acid-group, resulting in the concommitant reduction of iron(III) to biologically useful iron(II).[non-primary source needed]

3D structure of petrobactin-iron complex generated with OPLS-AA forcefield in MOE.[according to whom?][citation needed]

Chemical structures

Biological function

Like other siderophores, petrobactin is secreted by pathogenic bacterium infecting animals.[citation needed] In the case of B. anthracis, petrobactin is used to acquire iron from its host.[citation needed]

The yclNOPQ operon[where?] is required for the utilization of petrobactin.[non-primary source needed]

Orthologs of this operon likely contribute to the pathogenicity of Bacilli species.[clarification needed][non-primary source needed]

Mechanism of action

The 3,4-catecholate moieties of Bacillus petrobactin, terminal in the ligand, do not improve iron(III) affinity (relative to other siderophores with hydroxamate moieties);[verification needed] rather, they increase the rate of at which ferric iron is extracted from human transferrin.[relevant?][non-primary source needed]

Biosynthesis

In B. anthracis, petrobactin is produced by a nonribosomal peptide synthetase independent siderophore (NIS) synthetase pathway,[jargon] in a pathway termed "Asb" for "anthrax siderophore biosynthesis", based on the organism of its original characterisation.[non-primary source needed]

Biosynthesis of petrobactin in Bacillus anthracis. Reconstruction of figure 1C in Nusca, Tyler D. (2012).[non-primary source needed] Abbreviations used: ATP, AMP, PPi.

As indicated in the figure, biosynthesis in B. anthracis procedes with ATP-dependent, AsbA-mediated amide formation between a primary carboxylate of citric acid, and the terminal primary amine of the butane-1,4-diamine portion of spermidine,[non-primary source needed] via displacement reaction of an acylphosphate intermediate by the primary amino-group.[original research?][citation needed][non-primary source needed][better source needed] Separately, 3,4-dihydroxybenzoic acid is produced by AsbF from 3-dehydroshikimic acid, and this benzoic acid is used to produce a thioester intermediate with a cysteine residue of AsbD, a further ATP-dependent reaction catalysed by AsbC.[non-primary source needed][non-primary source needed]

From the citroyl-spermidine biosynthetic intermediate (AsbA reaction product), the process can proceed in one of two ways, either with (i) AsbB-mediated installation of a second spermidine moiety at the remaining free primary carboxylate of the AsbA product to give a symmetric bis-spermidyl-citrate, followed by sequential AsbE-catalysed installations, from AsbD-thioesters, of two 3,4-dihydroxybenzoyl moieties, as amides, at the two free primary amines of the AsbB product;[non-primary source needed] or, (ii) altering this order of reactions in first catalysing attachment of one AsbD-thioester-derived 3,4-dihydroxybenzoyl moiety by AsbE, then in performing the AsbB-catalysed attachment of the second spermidine moiety by its butane-1,4-diamine portion, followed (again) by AsbE-catalysed addition of the second AsbD-thioester-derived 3,4-dihydroxybenzoyl moiety.[non-primary source needed] In both of these variant reaction sequences, the AsbB-mediated amide-forming reactions are ATP-dependent, and the AsbE-mediated benzoylation reactions regenerate the free cysteinyl-thiol form of AsbD.[non-primary source needed][non-primary source needed] From both reaction sequences, the product is petrobactin, a symmetric citric acid derivative with 3,4-dihydroxybenzoyl-spermidine moieties attached to each of its primary carboxylic acids.[non-primary source needed]

Comparative bacterial genomics

The gene cluster encoding the Asb proteins in B. anthracis presents the individual genes in alphabetical order, AsbA through AsbF, an order identical to that seen in M. hydrocarbonclasticus biosynthesis of petrobactin.[non-primary source needed][verification needed] In A. macleodii only the first three genes, encoding the proteins AsbA through AsbC, are identical to B. anthracis; its versions of the genes encoding AsbD and AsbF are non-identical, and longer, and the cluster ends with its gene encoding AsbE, between which lie sequences encoding a PepSY domain, and sequences for two hypothetical protein domains.[non-primary source needed]

References

  1. ↑ KNApSAcK Database Staff (2026-06-30). "input word = C00043809" (database search query result). KNApSAcK Metabolite Information[clarification needed] (KNApSAcKfamily.com). Retrieved 2026-06-30. Note, the citation date is set to be the access-date that tihs page was viewed; the actual date of data in the database entry cannot be ascertained.[better source needed]
  2. 1 2 3 4 Manck, Lauren E.; Park, Jiwoon; Tully, Benjamin J.; Poire, Alfonso M.; Bundy, Randelle M.; Dupont, Christopher L.; Barbeau, Katherine A. (2021-08-02). "Petrobactin, A Siderophore Produced by Alteromonas, Mediates Community Iron Acquisition in the Global Ocean". The ISME Journal. 16 (2). Springer Science and Business Media LLC: 358–369. doi:10.1038/s41396-021-01065-y. ISSN 1751-7362. PMC 8776838. PMID 34341506.[non-primary source needed]
  3. ↑ Rue, Eden L.; Bruland, Kenneth W. (1995). "Complexation of Iron(III) by Natural Organic Ligands in the Central North Pacific as Determined by a New Competitive Ligand Equilibration/Adsorptive Cathodic Stripping Voltammetric Method". Marine Chemistry. 50 (1–4). Elsevier BV: 117–138. Bibcode:1995MarCh..50..117R. doi:10.1016/0304-4203(95)00031-l. ISSN 0304-4203.[non-primary source needed]
  4. ↑ Barbeau, Katherine; Zhang, Guangping; Live, David H.; Butler, Alison (2001-12-27). "Petrobactin, a Photoreactive Siderophore Produced by the Oil-Degrading Marine Bacterium Marinobacter hydrocarbonoclasticus". Journal of the American Chemical Society. 124 (3). American Chemical Society (ACS): 378–379. doi:10.1021/ja0119088. ISSN 0002-7863. PMID 11792199.[non-primary source needed]
  5. 1 2 Zawadzka, Anna M.; Kim, Youngchang; Maltseva, Natalia; Nichiporuk, Rita; Fan, Yao; Joachimiak, Andrzej; Raymond, Kenneth N. (2009-12-22). "Characterization of a Bacillus subtilis Transporter for Petrobactin, an Anthrax Stealth Siderophore". Proceedings of the National Academy of Sciences. 106 (51): 21854–21859. Bibcode:2009PNAS..10621854Z. doi:10.1073/pnas.0904793106. ISSN 0027-8424. PMC 2799803. PMID 19955416.[non-primary source needed]
  6. ↑ Abergel, Rebecca J.; Zawadzka, Anna M.; Raymond, Kenneth N. (2008-01-26). "Petrobactin-Mediated Iron Transport in Pathogenic Bacteria: Coordination Chemistry of an Unusual 3,4-Catecholate/Citrate Siderophore". Journal of the American Chemical Society. 130 (7). American Chemical Society (ACS): 2124–2125. Bibcode:2008JAChS.130.2124A. doi:10.1021/ja077202g. ISSN 0002-7863. PMID 18220393.[non-primary source needed]
  7. ↑ Carroll, Cassandra S.; Moore, Margo M. (2018-06-04). "Ironing Out Siderophore Biosynthesis: A Review of Non-Ribosomal Peptide Synthetase (NRPS)-Independent Siderophore Synthetases". Critical Reviews in Biochemistry and Molecular Biology. 53 (4): 356–381. doi:10.1080/10409238.2018.1476449. ISSN 1040-9238. PMID 29863423. S2CID 44093348.
  8. 1 2 3 4 5 6 7 8 Nusca, Tyler D.; Kim, Youngchang; Maltseva, Natalia; Lee, Jung Yeop; Eschenfeldt, William; Stols, Lucy; Schofield, Michael M.; Scaglione, Jamie B.; Dixon, Shandee D.; Oves-Costales, Daniel; Challis, Gregory L.; Hanna, Philip C.; Pfleger, Brian F.; Joachimiak, Andrzej; Sherman, David H. (2012). "Functional and Structural Analysis of the Siderophore Synthetase AsbB through Reconstitution of the Petrobactin Biosynthetic Pathway from Bacillus anthracis". Journal of Biological Chemistry. 287 (19). Elsevier BV: 16058–16072. doi:10.1074/jbc.m112.359349. ISSN 0021-9258. PMC 3346087. PMID 22408253.[non-primary source needed]
  9. 1 2 The amide-forming reactions are suggested to proceed via a displacement reaction of an acylphosphate intermediate of citric acid, by the primary amine nucleophile of spermidine; for these details, and a suggested series of thiol and amide nitrogen protonations and deprotonations,[original research?][citation needed] see Petchey, Mark R.; Grogan, Gideon (2019-08-08). "Enzyme-Catalysed Synthesis of Secondary and Tertiary Amides". Advanced Synthesis & Catalysis. 361 (17). Wiley: 3895–3914. doi:10.1002/adsc.201900694. ISSN 1615-4150. S2CID 199076147.[non-primary source needed][better source needed] Note, this source presents no relevant evidence regarding the biosynthesis of petrobactin.
  10. ↑ The dehydration of 3-dehydroshikimic acid to form 3,4-dihydroxybenzoic acid has been suggested to proceed via a dienol benzene rearrangement followed by reduction to aromatize the ring.[original research?][citation needed] See Gentles, Margaret Jevnik; Moss, Jane B.; Herzog, Hershel L.; Hershberg, E. B. (1958). "The Dienol-Benzene Rearrangement.1 Some Chemistry of 1,4-Androstadiene-3,17-dione". Journal of the American Chemical Society. 80 (14). American Chemical Society (ACS): 3702–3705. Bibcode:1958JAChS..80.3702G. doi:10.1021/ja01547a058. ISSN 0002-7863.[non-primary source needed][better source needed] Note, this source does not speak to the dehydration of dehydroshikimic acid.