The Interconversion of the 5,6,7,8-Tetrahydro-, 7,8-Dihydro-, and Radical Forms of 6,6,7,7-Tetramethyldihydropterin. A Model for the Biopterin Center of Aromatic Amino Acid Mixed Function Oxidases

Gert Eberlein, Thomas C. Bruice, R. A. Lazarus, Robert Henrie, Stephen Benkovic

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Abstract

The 6,7-blocked pterins 6,6,7,7-tetramethyl-5,6,7,8-tetrahydropterin (1red). 6,6,7,7-tetramethyl-7,8-dihydropterin (1ox), and 5,6,6,7,7-pentamethyl-5,6,7,8-tetrahydropterin (2red) have been synthesized. 1ox represents the quinonoid product obtained upon 2e oxidation (electrochemical, Br2) of 1red. Two-electron oxidation of 2red yields 1ox, rather than 2ox due to the rapid demethylation of the latter (the pseudo-first-order rate constant determined from elelectrochemical measurements at pH 5.9 is 1.4 × 10−2 s−1). Solvolysis of 1ox yields the ring contracted imidazolone 3ox (Scheme III). The acid-base and spectral properties of 1red (Scheme I), 1ox (Scheme II), and 2red (Scheme IV) are described. The comproportionation equilibrium constant for the formation of the pterin radical 1sem has been determined by spectral and EPR measurements. The comproportionation constant for formation of 1sem from 1red and 1ox is much smaller (~107-fold at pH 1.0 and ~102-fold at pH 7.0) than the like constants for flavin radical formation. The pH dependence of the redox potentials associated with 2e interconversion of 1red and 1ox has been determined and the like dependence of the le redox potentials for the interconversion of 1red, 1sem, and 1ox have been approximated. At scan speeds of 50 mV/s and at pH 5.9, the oxidation of 2red to 2ox can be shown to represent two 1e transfer steps in both anodic and cathodic sweeps. Nernst-Clark plots of potential vs. pH for 1 and 2 are provided (Figure 6). The mechanism of reaction of 1red and 2red with O2 has been explored by comparing ΔG (from initial rates) to ΔG° values (electrochemical calculations) for 1e transfer from the tetrahydropterins to O2. Since the difference ΔG – ΔG° is very small (13 kJ M−1) and protons are not involved in the critical transition state, it is concluded that the transition state closely resembles the radical pairs {lsemO2} and {2semO2·} which must couple to provide 4a-hydroperoxypterins. The hydroperoxide moiety is consumed in the overall autocatalytic oxidation of 1red and 2red.

Original languageEnglish (US)
Pages (from-to)7916-7924
Number of pages9
JournalJournal of the American Chemical Society
Volume106
Issue number25
DOIs
StatePublished - Dec 1 1984

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Biopterin
Aromatic Amino Acids
Mixed Function Oxygenases
Carboxylic acids
Pterins
Amino acids
Oxidation
Electrochemical oxidation
Equilibrium constants
Hydrogen Peroxide
Oxidation-Reduction
Paramagnetic resonance
Protons
Rate constants
Acids
Electrons
tetrahydropterin
Oxidoreductases

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

@article{7d1b6a8a05b14de3b29fefef3caf8b86,
title = "The Interconversion of the 5,6,7,8-Tetrahydro-, 7,8-Dihydro-, and Radical Forms of 6,6,7,7-Tetramethyldihydropterin. A Model for the Biopterin Center of Aromatic Amino Acid Mixed Function Oxidases",
abstract = "The 6,7-blocked pterins 6,6,7,7-tetramethyl-5,6,7,8-tetrahydropterin (1red). 6,6,7,7-tetramethyl-7,8-dihydropterin (1ox), and 5,6,6,7,7-pentamethyl-5,6,7,8-tetrahydropterin (2red) have been synthesized. 1ox represents the quinonoid product obtained upon 2e− oxidation (electrochemical, Br2) of 1red. Two-electron oxidation of 2red yields 1ox, rather than 2ox due to the rapid demethylation of the latter (the pseudo-first-order rate constant determined from elelectrochemical measurements at pH 5.9 is 1.4 × 10−2 s−1). Solvolysis of 1ox yields the ring contracted imidazolone 3ox (Scheme III). The acid-base and spectral properties of 1red (Scheme I), 1ox (Scheme II), and 2red (Scheme IV) are described. The comproportionation equilibrium constant for the formation of the pterin radical 1sem has been determined by spectral and EPR measurements. The comproportionation constant for formation of 1sem from 1red and 1ox is much smaller (~107-fold at pH 1.0 and ~102-fold at pH 7.0) than the like constants for flavin radical formation. The pH dependence of the redox potentials associated with 2e− interconversion of 1red and 1ox has been determined and the like dependence of the le− redox potentials for the interconversion of 1red, 1sem, and 1ox have been approximated. At scan speeds of 50 mV/s and at pH 5.9, the oxidation of 2red to 2ox can be shown to represent two 1e− transfer steps in both anodic and cathodic sweeps. Nernst-Clark plots of potential vs. pH for 1 and 2 are provided (Figure 6). The mechanism of reaction of 1red and 2red with O2 has been explored by comparing ΔG‡ (from initial rates) to ΔG° values (electrochemical calculations) for 1e− transfer from the tetrahydropterins to O2. Since the difference ΔG‡ – ΔG° is very small (13 kJ M−1) and protons are not involved in the critical transition state, it is concluded that the transition state closely resembles the radical pairs {lsemO2−} and {2semO2™·} which must couple to provide 4a-hydroperoxypterins. The hydroperoxide moiety is consumed in the overall autocatalytic oxidation of 1red and 2red.",
author = "Gert Eberlein and Bruice, {Thomas C.} and Lazarus, {R. A.} and Robert Henrie and Stephen Benkovic",
year = "1984",
month = "12",
day = "1",
doi = "10.1021/ja00337a047",
language = "English (US)",
volume = "106",
pages = "7916--7924",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "25",

}

The Interconversion of the 5,6,7,8-Tetrahydro-, 7,8-Dihydro-, and Radical Forms of 6,6,7,7-Tetramethyldihydropterin. A Model for the Biopterin Center of Aromatic Amino Acid Mixed Function Oxidases. / Eberlein, Gert; Bruice, Thomas C.; Lazarus, R. A.; Henrie, Robert; Benkovic, Stephen.

In: Journal of the American Chemical Society, Vol. 106, No. 25, 01.12.1984, p. 7916-7924.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Interconversion of the 5,6,7,8-Tetrahydro-, 7,8-Dihydro-, and Radical Forms of 6,6,7,7-Tetramethyldihydropterin. A Model for the Biopterin Center of Aromatic Amino Acid Mixed Function Oxidases

AU - Eberlein, Gert

AU - Bruice, Thomas C.

AU - Lazarus, R. A.

AU - Henrie, Robert

AU - Benkovic, Stephen

PY - 1984/12/1

Y1 - 1984/12/1

N2 - The 6,7-blocked pterins 6,6,7,7-tetramethyl-5,6,7,8-tetrahydropterin (1red). 6,6,7,7-tetramethyl-7,8-dihydropterin (1ox), and 5,6,6,7,7-pentamethyl-5,6,7,8-tetrahydropterin (2red) have been synthesized. 1ox represents the quinonoid product obtained upon 2e− oxidation (electrochemical, Br2) of 1red. Two-electron oxidation of 2red yields 1ox, rather than 2ox due to the rapid demethylation of the latter (the pseudo-first-order rate constant determined from elelectrochemical measurements at pH 5.9 is 1.4 × 10−2 s−1). Solvolysis of 1ox yields the ring contracted imidazolone 3ox (Scheme III). The acid-base and spectral properties of 1red (Scheme I), 1ox (Scheme II), and 2red (Scheme IV) are described. The comproportionation equilibrium constant for the formation of the pterin radical 1sem has been determined by spectral and EPR measurements. The comproportionation constant for formation of 1sem from 1red and 1ox is much smaller (~107-fold at pH 1.0 and ~102-fold at pH 7.0) than the like constants for flavin radical formation. The pH dependence of the redox potentials associated with 2e− interconversion of 1red and 1ox has been determined and the like dependence of the le− redox potentials for the interconversion of 1red, 1sem, and 1ox have been approximated. At scan speeds of 50 mV/s and at pH 5.9, the oxidation of 2red to 2ox can be shown to represent two 1e− transfer steps in both anodic and cathodic sweeps. Nernst-Clark plots of potential vs. pH for 1 and 2 are provided (Figure 6). The mechanism of reaction of 1red and 2red with O2 has been explored by comparing ΔG‡ (from initial rates) to ΔG° values (electrochemical calculations) for 1e− transfer from the tetrahydropterins to O2. Since the difference ΔG‡ – ΔG° is very small (13 kJ M−1) and protons are not involved in the critical transition state, it is concluded that the transition state closely resembles the radical pairs {lsemO2−} and {2semO2™·} which must couple to provide 4a-hydroperoxypterins. The hydroperoxide moiety is consumed in the overall autocatalytic oxidation of 1red and 2red.

AB - The 6,7-blocked pterins 6,6,7,7-tetramethyl-5,6,7,8-tetrahydropterin (1red). 6,6,7,7-tetramethyl-7,8-dihydropterin (1ox), and 5,6,6,7,7-pentamethyl-5,6,7,8-tetrahydropterin (2red) have been synthesized. 1ox represents the quinonoid product obtained upon 2e− oxidation (electrochemical, Br2) of 1red. Two-electron oxidation of 2red yields 1ox, rather than 2ox due to the rapid demethylation of the latter (the pseudo-first-order rate constant determined from elelectrochemical measurements at pH 5.9 is 1.4 × 10−2 s−1). Solvolysis of 1ox yields the ring contracted imidazolone 3ox (Scheme III). The acid-base and spectral properties of 1red (Scheme I), 1ox (Scheme II), and 2red (Scheme IV) are described. The comproportionation equilibrium constant for the formation of the pterin radical 1sem has been determined by spectral and EPR measurements. The comproportionation constant for formation of 1sem from 1red and 1ox is much smaller (~107-fold at pH 1.0 and ~102-fold at pH 7.0) than the like constants for flavin radical formation. The pH dependence of the redox potentials associated with 2e− interconversion of 1red and 1ox has been determined and the like dependence of the le− redox potentials for the interconversion of 1red, 1sem, and 1ox have been approximated. At scan speeds of 50 mV/s and at pH 5.9, the oxidation of 2red to 2ox can be shown to represent two 1e− transfer steps in both anodic and cathodic sweeps. Nernst-Clark plots of potential vs. pH for 1 and 2 are provided (Figure 6). The mechanism of reaction of 1red and 2red with O2 has been explored by comparing ΔG‡ (from initial rates) to ΔG° values (electrochemical calculations) for 1e− transfer from the tetrahydropterins to O2. Since the difference ΔG‡ – ΔG° is very small (13 kJ M−1) and protons are not involved in the critical transition state, it is concluded that the transition state closely resembles the radical pairs {lsemO2−} and {2semO2™·} which must couple to provide 4a-hydroperoxypterins. The hydroperoxide moiety is consumed in the overall autocatalytic oxidation of 1red and 2red.

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