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Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism.

Frère F, Schubert WD, Stauffer F, Frankenberg N, Neier R, Jahn D, Heinz DW
J Mol Biol 320 237-47 (2002)
Cited: 32 times
EuropePMC logo PMID: 12079382

Abstract

All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen (PBG) as a common precursor. Porphobilinogen synthase (PBGS) synthesizes PBG through the asymmetric condensation of two molecules of aminolevulinic acid (ALA). Crystal structures of PBGS from various sources confirm the presence of two distinct binding sites for each ALA molecule, termed A and P. We have solved the structure of the active-site variant D139N of the Mg2+-dependent PBGS from Pseudomonas aeruginosa in complex with the inhibitor 5-fluorolevulinic acid at high resolution. Uniquely, full occupancy of both substrate binding sites each by a single substrate-like molecule was observed. Both inhibitor molecules are covalently bound to two conserved, active-site lysine residues, Lys205 and Lys260, through Schiff bases. The active site now also contains a monovalent cation that may critically enhance enzymatic activity. Based on these structural data, we postulate a catalytic mechanism for P. aeruginosa PBGS initiated by a C-C bond formation between A and P-side ALA, followed by the formation of the intersubstrate Schiff base yielding the product PBG.

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  2. Plastid-associated porphobilinogen synthase from Toxoplasma gondii: kinetic and structural properties validate therapeutic potential. Shanmugam D, Wu B, Ramirez U, Jaffe EK, Roos DS. J Biol Chem 285 22122-22131 (2010)
  3. Rhodobacter capsulatus porphobilinogen synthase, a high activity metal ion independent hexamer. Bollivar DW, Clauson C, Lighthall R, Forbes S, Kokona B, Fairman R, Kundrat L, Jaffe EK. BMC Biochem 5 17 (2004)
  4. Crystal structure of Toxoplasma gondii porphobilinogen synthase: insights on octameric structure and porphobilinogen formation. Jaffe EK, Shanmugam D, Gardberg A, Dieterich S, Sankaran B, Stewart LJ, Myler PJ, Roos DS. J Biol Chem 286 15298-15307 (2011)
  5. Probing the oligomeric assemblies of pea porphobilinogen synthase by analytical ultracentrifugation. Kokona B, Rigotti DJ, Wasson AS, Lawrence SH, Jaffe EK, Fairman R. Biochemistry 47 10649-10656 (2008)
  6. Rapid catalytic template searching as an enzyme function prediction procedure. Nilmeier JP, Kirshner DA, Wong SE, Lightstone FC. PLoS One 8 e62535 (2013)
  7. The Remarkable Character of Porphobilinogen Synthase. Jaffe EK. Acc Chem Res 49 2509-2517 (2016)
  8. Docking to large allosteric binding sites on protein surfaces. Ramirez UD, Myachina F, Stith L, Jaffe EK. Adv Exp Med Biol 680 481-488 (2010)
  9. Impact of quaternary structure dynamics on allosteric drug discovery. Jaffe EK. Curr Top Med Chem 13 55-63 (2013)
  10. wALADin benzimidazoles differentially modulate the function of porphobilinogen synthase orthologs. Lentz CS, Halls VS, Hannam JS, Strassel S, Lawrence SH, Jaffe EK, Famulok M, Hoerauf A, Pfarr KM. J Med Chem 57 2498-2510 (2014)
  11. The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study. Nogara PA, Orian L, Rocha JBT. Comput Toxicol 15 100127 (2020)


Reviews citing this publication (4)

  1. The biochemistry of heme biosynthesis. Heinemann IU, Jahn M, Jahn D. Arch Biochem Biophys 474 238-251 (2008)
  2. Structure and function of enzymes in heme biosynthesis. Layer G, Reichelt J, Jahn D, Heinz DW. Protein Sci 19 1137-1161 (2010)
  3. Morpheeins--a new structural paradigm for allosteric regulation. Jaffe EK. Trends Biochem Sci 30 490-497 (2005)
  4. The porphobilinogen synthase catalyzed reaction mechanism. Jaffe EK. Bioorg Chem 32 316-325 (2004)

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  1. Control of tetrapyrrole biosynthesis by alternate quaternary forms of porphobilinogen synthase. Breinig S, Kervinen J, Stith L, Wasson AS, Fairman R, Wlodawer A, Zdanov A, Jaffe EK. Nat Struct Biol 10 757-763 (2003)
  2. Strain-Level Differences in Porphyrin Production and Regulation in Propionibacterium acnes Elucidate Disease Associations. Johnson T, Kang D, Barnard E, Li H. mSphere 1 e00023-15 (2016)
  3. An unusual phylogenetic variation in the metal ion binding sites of porphobilinogen synthase. Jaffe EK. Chem Biol 10 25-34 (2003)
  4. Delta-aminolevulinic acid dehydratase from Plasmodium falciparum: indigenous versus imported. Dhanasekaran S, Chandra NR, Chandrasekhar Sagar BK, Rangarajan PN, Padmanaban G. J Biol Chem 279 6934-6942 (2004)
  5. Structure of the heme biosynthetic Pseudomonas aeruginosa porphobilinogen synthase in complex with the antibiotic alaremycin. Heinemann IU, Schulz C, Schubert WD, Heinz DW, Wang YG, Kobayashi Y, Awa Y, Wachi M, Jahn D, Jahn M. Antimicrob Agents Chemother 54 267-272 (2010)
  6. X-ray structure of a putative reaction intermediate of 5-aminolaevulinic acid dehydratase. Erskine PT, Coates L, Butler D, Youell JH, Brindley AA, Wood SP, Warren MJ, Shoolingin-Jordan PM, Cooper JB. Biochem J 373 733-738 (2003)
  7. The activation mechanism of human porphobilinogen synthase by 2-mercaptoethanol: intrasubunit transfer of a reserve zinc ion and coordination with three cysteines in the active center. Sawada N, Nagahara N, Sakai T, Nakajima Y, Minami M, Kawada T. J Biol Inorg Chem 10 199-207 (2005)
  8. Tracking the evolution of porphobilinogen synthase metal dependence in vitro. Frère F, Reents H, Schubert WD, Heinz DW, Jahn D. J Mol Biol 345 1059-1070 (2005)
  9. Association between delta-aminolevulinic acid dehydratase polymorphism and placental lead levels. Kayaaltı Z, Sert S, Kaya-Akyüzlü D, Söylemez E, Söylemezoğlu T. Environ Toxicol Pharmacol 41 147-151 (2016)
  10. Synthesis of bisubstrate inhibitors of porphobilinogen synthase from Pseudomonas aeruginosa. Gacond S, Frère F, Nentwich M, Faurite JP, Frankenberg-Dinkel N, Neier R. Chem Biodivers 4 189-202 (2007)
  11. Towards Initial Indications for a Thiol-Based Redox Control of Arabidopsis 5-Aminolevulinic Acid Dehydratase. Wittmann D, Kløve S, Wang P, Grimm B. Antioxidants (Basel) 7 E152 (2018)
  12. Redox and metal-regulated oligomeric state for human porphobilinogen synthase activation. Sawada N, Nagahara N, Arisaka F, Mitsuoka K, Minami M. Amino Acids 41 173-180 (2011)
  13. Formation of protoporphyrin IX from carboxylic- and amino-derivatives of 5-aminolevulinic acid. Kaliszewski M, Juzeniene A, Juzenas P, Kwasny M, Kaminski J, Dabrowski Z, Golinski J, Moan J. Photodiagnosis Photodyn Ther 2 129-134 (2005)
  14. Probing the active site of rat porphobilinogen synthase using newly developed inhibitors. Li N, Chu X, Liu X, Li D. Bioorg Chem 37 33-40 (2009)
  15. Synthesis and antibacterial activity of alaremycin derivatives for the porphobilinogen synthase. Iwai N, Nakayama K, Oku J, Kitazume T. Bioorg Med Chem Lett 21 2812-2815 (2011)
  16. Biochemical and molecular characterization of a novel porphobilinogen synthase from Corynebacterium glutamicum. Zhu D, Wu C, Niu C, Li H, Ge F, Li W. World J Microbiol Biotechnol 39 165 (2023)
  17. Comparison of ALAD activities of Citrobacter and Pseudomonas strains and their usage as biomarker for Pb contamination. Ciğerci IH, Korcan SE, Konuk M, Oztürk S. Environ Monit Assess 139 41-48 (2008)


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