Substituent Effects on Carbon Acidity in Aqueous Solution and at Enzyme Active Sites

Abstract

Methods are described for the determination of pKas for weak carbon acids in water. The application of these methods to the determination of the pKas for a variety of carbon acids including nitriles, imidazolium cations, amino acids, peptides and their derivatives and, α-iminium cations is presented. The substituent effects on the acidity of these different classes of carbon acids are discussed; and, the relevance of these results to catalysis of the deprotonation of amino acids by enzymes and by pyridoxal 5′-phosphate is reviewed. The procedure for estimating the pKa of uridine 5′-phosphate for C-6 deprotonation at the active site of orotidine 5′-phosphate decarboxylase is described, and the effect of a 5-F substituent on carbon acidity of the enzyme-bound substrate is discussed.

Thiolase: A Versatile Biocatalyst Employing Coenzyme A–Thioester Chemistry for Making and Breaking C–C Bonds

“…This reactivity is enhanced when the thioester oxygen is bound in an oxyanion hole (OAH) of an enzyme active site, which stabilizes the negative charge of the thioester oxyanion. Lynen (26) already pointed out that the pK of the α proton of a thioester (also referred to as the C2 proton) (Figure 3) is lower than the corresponding pK of an oxygen ester, recently estimated to be 21.0 and 25.6, respectively (44,45). In general, oxygen esters are less reactive than sulfur esters (due to the larger size of the sulfur atom) (46,47), and sulfur esters are not very stable at high pH (48).…”

“…pathways of glucose, amino acids, and fatty acids and is subsequently used in pathways for the synthesis of various compounds, including fatty acids, cholesterol, and ketone bodies, as well as for the generation of energy via the Krebs cycle. The reactivity of the C1 and C2 atoms of the thioester moiety of acetyl-CoA (Figure 3) has been the topic of many studies (43,44). This reactivity is enhanced when the thioester oxygen is bound in an oxyanion hole (OAH) of an enzyme active site, which stabilizes the negative charge of the thioester oxyanion.…”

S-Adenosylmethionine: more than just a methyl donor

“…108,109 In principle, SAM should also be capable of a favorable 3-exo-tet cyclization to form 1-aminocyclopropane-1carboxylic acid (ACC, 46) again with the elimination of MTA if it were not for the nonacidic C-a proton, which has a pK a of approximately 29. 230 ACC is indeed found as a metabolite from SAM in plants and is the precursor to the important plant hormone ethylene. [231][232][233] This difficulty with deprotonation has been overcome in the case of plant ACC synthase by acidifying C1 via formation of an external aldimine with PLP (167).…”

Umpolung in reactions catalyzed by thiamine pyrophosphate dependent enzymes

“…The carbene stabilized by adjacent heteroatoms (Hanson, 1987;Prier & Arnold, 2015;Heidari, Howe & Kluger, 2016) reacts as a strong nucleophile, by addition with the carbonyl group of a metabolite (Broderick, 2001;Amyes & Richard, 2017). In absence of the apoenzyme, TPP decarboxylates pyruvic acid at room temperature at pH 8.4 (Mizuhara, Tamura & Arata, 1951;Breslow, 1958).…”