Glycine Enolates:  The Large Effect of Iminium Ion Formation on α-Amino Carbon Acidity

Ríos, Ana; Crugeiras, Juan; Amyes, Tina L.; Richard, John P.

doi:10.1021/ja016250c

Cited by 58 publications

(129 citation statements)

References 18 publications

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“…By contrast, www.chemeurj.org when the experiment was performed with the metallacycle 9, which does not contain the COOR fragment, no reaction was observed (Scheme 2), a result suggesting that the acidity of the H a atom is essential to the oxidative cleavage of the nitrogen-carbon bond of the amino acid fragment. It has recently been reported that the acidity of the aamino carbon atom of the glycine moiety is dramatically increased by the formation of the iminium ion adduct to acetone, [28] and our results suggest that the coordination of the imine to a palladium atom can also result in an increase of the acidity of the H a atom. These reasons prompted us to investigate the exchange for deuterium of the a-proton of the amino acid moiety in the metallacycle 3 a.…”

Section: Resultssupporting

confidence: 78%

Deamination of the Amino Acid Fragment in Imine Metallacycles: Unexpected Synthesis of an NH‐Aldimine Organometallic Compound

Albert

Cadena

González

et al. 2006

Chemistry A European J

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We report that the action of Lewis bases, such as triphenylphosphine, pyridine, or trimethylamine, on imine metallacycles derived from amino acids leads to the formation of the first organometallic compound of an NH aldimine, a highly reactive organic species, and the corresponding alpha-ketoester, in a deamination reaction that mimics the metabolism of alpha-amino acids. The synthesis of different cyclopalladated compounds by a reaction between palladium acetate and the Schiff bases 2,4,6-Me(3)C(6)H(2)CH=NCH(R(1))COOR(2) (R(1) = CH(2)Ph, R(2) = Et and R(1) = Ph, R(2) = Me) is also reported.

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Section: Resultssupporting

confidence: 78%

Deamination of the Amino Acid Fragment in Imine Metallacycles: Unexpected Synthesis of an NH‐Aldimine Organometallic Compound

Albert

Cadena

González

et al. 2006

Chemistry A European J

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“…The immediate microenvironment of Tyr 363 in the active site is not hydrophobic consisting of charged residues and a water molecule that would argue for a solution pK a ϳ 10.5 for Tyr 363 and is supported by a proposed pK a Ͼ 9 for the basic group involved in ␣-proton abstraction in muscle aldolase (33). A pK a ϳ 18 has been estimated for the ionization at DHAP C3 (34), which in the iminium would be lowered to a value approaching that of a tyrosine (35)(36)(37), favoring proton transfer by matching pK a values. Overlay of the K146M-DHAP and WT-P i structures onto the WT-FBP structure (15) positions the C terminus Tyr 363 hydroxyl in close contact with the C4 atom of the FBP molecule (Fig.…”

Section: Discussionmentioning

confidence: 93%

“…The Arg 148 side chain further stabilizes attachment by hydrogen bonding with the His 361 backbone carbonyl. In the closed conformation, the helix flanking the active site (residues [33][34][35][36][37][38][39][40][41][42][43][44][45] and interacting with the C-terminal region not only narrows the active site cleft but also shifts by ϳ0.5 Å outwards along its helical axis relative to the structure of the enamine.…”

Section: Resultsmentioning

confidence: 99%

Stereospecific Proton Transfer by a Mobile Catalyst in Mammalian Fructose-1,6-bisphosphate Aldolase

St-Jean¹,

Sygusch

2007

Journal of Biological Chemistry

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Class I fructose-1,6-bisphosphate aldolases catalyze the interconversion between the enamine and iminium covalent enzymatic intermediates by stereospecific exchange of the pro(S) proton of the dihydroxyacetone-phosphate C3 carbon, an obligatory reaction step during substrate cleavage. To investigate the mechanism of stereospecific proton exchange, high resolution crystal structures of native and a mutant Lys 146 Stereospecificity is one of the hallmarks of enzyme catalysis. Aldolases, which are abundant and ubiquitous enzymes, catalyze stereospecific carbon-carbon bond formation, one of the most important transformations in living organisms. Their role is best known in glycolysis where fructose-1,6-bis(phosphate) (FBP) 3 aldolases (EC 4.1.2.13) promote the cleavage of FBP to triose phosphates, D-glyceraldehyde-3-phosphate (G3P), and dihydroxyacetone phosphate (DHAP). A common feature to class I enzymes is the use of a covalent mechanism for catalysis implicating iminium (protonated Schiff base) formation between a lysine residue on the enzyme and a ketose substrate (1) that entails stereospecific proton exchange in the covalent intermediate (2). Of the three aldolase isozymes found in vertebrates (3), the catalytic mechanism has been extensively studied using class I aldolase A from rabbit muscle and key intermediates are depicted in reaction Scheme 1.In the condensation direction, the reaction involves covalent intermediate formation with the keto triose phosphate DHAP followed by condensation with the aldehyde G3P to form the ketose of the acyclic FBP substrate (4, 5). To form the C3-C4 bond of FBP, the enzyme stereospecifically abstracts the pro(S) C3 proton of the trigonal iminium 1 (6, 7) that is formed from the Michaelis complex with DHAP thereby generating via the enamine 2 (2) the carbanionic character at C3 of DHAP for the aldol reaction. The nascent carbon-carbon bond has the same orientation as the pro(S) ␣-hydrogen initially abstracted from the DHAP imine intermediate. The overall retention of configuration at C3 requires that proton abstraction from 1 to yield the enamine 2 and condensation with aldehyde in 3 must take place from the same direction on the enzyme (8). The iminium intermediate formed is then hydrolyzed and FBP is released by the inverse reaction sequence shown in Scheme 1.A distinguishing mechanistic feature of class I aldolases is the relative stability of the iminium 1 and enamine 2 forms, which is a consequence of the catalytic requirements. The enzyme must stabilize the enamine 2 and/or the preceding iminium 1 such that no decomposition occurs prior to reaction with the aldehyde as shown in 3. This stability is reflected in solution where the enzymatic populations 1 and 2 represent 20 and 60%, respectively, of bound DHAP on the muscle enzyme under equilibrium conditions (9). The interconversion between the two forms implicates the conserved C-terminal Tyr 363 residue whose proteolysis inhibits the stereospecific proton exchange step, making it rate-limiting (10), whereas the pen...

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“…For example a pK a of 14 was estimated for deprotonation of the α-imino carbon of the iminium ion adduct between acetone and glycine methyl ester. 8 The ca 8-unit lower pK a estimated for the α-imino carbon of 2-H 4 reflects specific stabilization of charge by the elaborate electron sink of the pyridoxal cofactor. It is not possible to generate a significant concentration of this "quininoid"-type carbanion by deprotonation of 2-H 4 , because 2-H 4 only accumulates at a pH 3 that is below the pK a for the carbon acid.…”

Section: Substituent Effects On the Acidity Of Glycinementioning

confidence: 99%

Covalent Catalysis by Pyridoxal: Evaluation of the Effect of the Cofactor on the Carbon Acidity of Glycine

Tóth

Richard

2007

J. Am. Chem. Soc.

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First-order rate constants for deprotonation of the α-imino carbon of the adduct between 5′-deoxypyridoxal (1) and glycine were determined as the rate constants for Claisen-type addition of glycine to 1 where deprotonation is rate determining for product formation. There is no significant deprotonation at pH 7.1 of the form of the 1-glycine iminium ion with the pyridine nitrogen in the basic form. The value of k HO for hydroxide ion-catalyzed deprotonation of the α-imino carbon increases from 7.5 × 10 2 to 3.8 × 10 5 to 3.0 × 10 7 M -1 s -1 , respectively, with protonation of the pyridine nitrogen, the phenoxide oxyanion and the carboxylate anion of the 1-glycine iminium ion. There is a corresponding decrease in the pK a s for deprotonation of the α-imino carbon from 17 to 11 to 6. It is proposed that enzymes selectively bind and catalyze the reaction of the iminium ion with pK a = 17. A comparison of k B = 1.7 × 10 -3 s -1 for deprotonation of the α-imino carbon of this cofactorglycine adduct (pK a = 17 by HPO 4 2-with k cat /K m = 4 × 10 5 M -1 s -1 for catalysis of amino-acid racemization by alanine racemase shows that the enzyme causes a ca 2 × 10 8 -fold acceleration of the rate of deprotonation the α-imino carbon. This corresponds to about one-half of the burden borne by alanine racemase in catalysis of deprotonation of alanine.

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Glycine Enolates: The Large Effect of Iminium Ion Formation on α-Amino Carbon Acidity

Cited by 58 publications

References 18 publications

Deamination of the Amino Acid Fragment in Imine Metallacycles: Unexpected Synthesis of an NH‐Aldimine Organometallic Compound

Deamination of the Amino Acid Fragment in Imine Metallacycles: Unexpected Synthesis of an NH‐Aldimine Organometallic Compound

Stereospecific Proton Transfer by a Mobile Catalyst in Mammalian Fructose-1,6-bisphosphate Aldolase

Covalent Catalysis by Pyridoxal: Evaluation of the Effect of the Cofactor on the Carbon Acidity of Glycine

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