title: The Porphobilinogen Conundrum in Prebiotic Routes to Tetrapyrrole Macrocycles.
abstract: 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.
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695-8204, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Chemistry and Biochemistry, University of Maryland Baltimore County, Baltimore, MD, 21250-0001, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Ptaszek
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695-8204, USA.
authors.forename: Vanampally
authors.initials: V
authors.lastname: Chandrashaker
authors.affiliation: Department of Chemistry, North Carolina State University, Raleigh, NC, 27695-8204, USA. jlindsey@ncsu.edu.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lindsey
mesh_terms: D000622:Aminolevulinic Acid / Q000031:analogs & derivatives* / Q000737:chemistry; D019418:Evolution, Chemical; D007700:Kinetics; D000069497:Origin of Life; D011162:Porphobilinogen / Q000737:chemistry*; D045725:Tetrapyrroles / Q000737:chemistry*
chemical_list: D045725:Tetrapyrroles; D011162:Porphobilinogen; D000622:Aminolevulinic Acid
keywords: Biomimetic; Biosynthesis; DFT; Porphyrin; Porphyrinogen; δ-aminolevulinic acid