Origins of Life and Evolution of Biospheres

, Volume 47, Issue 1, pp 93–119 | Cite as

The Porphobilinogen Conundrum in Prebiotic Routes to Tetrapyrrole Macrocycles

  • Masahiko Taniguchi
  • Marcin Ptaszek
  • Vanampally Chandrashaker
  • Jonathan S. Lindsey
Prebiotic Chemistry


Attempts to develop a credible prebiotic route to tetrapyrroles have relied on enzyme-free recapitulation of the extant biosynthesis, but this process has foundered from the inability to form the pyrrole porphobilinogen (PBG) in good yield by self-condensation of the precursor δ-aminolevulinic acid (ALA). PBG undergoes robust oligomerization in aqueous solution to give uroporphyrinogen (4 isomers) in good yield. ALA, PBG, and uroporphyrinogen III are universal precursors to all known tetrapyrrole macrocycles. The enzymic formation of PBG entails carbon-carbon bond formation between the less stable enolate/enamine of one ALA molecule (3-position) and the carbonyl/imine (4-position) of the second ALA molecule; without enzymes, the first ALA reacts at the more stable enolate/enamine (5-position) and gives the pyrrole pseudo-PBG. pseudo-PBG cannot self-condense, yet has one open α-pyrrole position and is proposed to be a terminator of oligopyrromethane chain-growth from PBG. Here, 23 analogues of ALA have been subjected to density functional theoretical (DFT) calculations, but no motif has been identified that directs reaction at the 3-position. Deuteriation experiments suggested 5-(phosphonooxy)levulinic acid would react preferentially at the 3- versus 5-position, but a hybrid condensation with ALA gave no observable uroporphyrin. The results suggest efforts toward a biomimetic, enzyme-free route to tetrapyrroles from ALA should turn away from structure-directed reactions and focus on catalysts that orient the two aminoketones to form PBG in a kinetically controlled process, thereby avoiding formation of pseudo-PBG.


δ-aminolevulinic acid Porphyrinogen Porphyrin DFT Biosynthesis Biomimetic 



This work was supported by a grant from the NSF Chemistry of Life Processes Program (NSF CHE-0953010). Exploratory studies of the conversion of ALA to PBG and uroporphyrins were conducted by J. S. L. as Guest Investigator at The Rockefeller University in 1990–1991. Mass spectra were obtained at the Mass Spectrometry Laboratory for Biotechnology at North Carolina State University. Partial funding for the facility was obtained from the North Carolina Biotechnology Center and the National Science Foundation.


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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Masahiko Taniguchi
    • 1
  • Marcin Ptaszek
    • 2
  • Vanampally Chandrashaker
    • 1
  • Jonathan S. Lindsey
    • 1
  1. 1.Department of ChemistryNorth Carolina State UniversityRaleighUSA
  2. 2.Department of Chemistry and BiochemistryUniversity of Maryland Baltimore CountyBaltimoreUSA

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