Acetylation, abnormal products

Dakin, H. D. West, R. J. Biol. Chem. 1928, 78, 91, 745, and 757. In 1928, Henry Dakin and Rudolf West, a clinician, reported on the reaction of a-amino acids with acetic anhydride to give a-acetamido ketones via azalactone intermediates. Interestingly, one year before this paper by Dakin and West, Levene and Steiger had observed both tyrosine and a-phenylananine gave abnormal products when acetylated under these conditions.Unfortunately, they were slow to identify the products and lost an opportunity to be immortalized by a name reaction. 

When the catalytic reaction of 6-hydroxymellein synthase is carried out in the absence of NADPH or with monomeric enzyme, keto-reduction of the carbonyl group of the triketomethylene chain does not take place, and the synthase liberates triacetic acid lactone instead of 6-hydroxymellein [64, 71]. However, the efficiencies of product formation are markedly lower than for the normal reaction. Two mechanisms could account for the low efficiency of triacetic acid lactone formation observed in the monomeric and the NADPH-depleted dimeric forms of 6-hydroxymellein synthase. These are 1) Reduced affinity of the cosubstrates acetyl-CoA and/or malonyl-CoA for the enzyme protein with the incomplete reaction centers 2) Reduced rate of reaction of acyl-CoA condensation and/or product liberation. To examine these possibilities, kinetic parameters of the two triacetic acid lactone-forming reactions were compared with those of the normal reaction which produces 6-hydroxymellein. The Km value of 6-hydroxymellein synthase for acetyl-CoA in the normal reaction was estimated to be 22 pM, while in both the NADPH-depleted dimer and the monomer reactions the affinity of 6-hydroxymellein synthase protein for acetyl-CoA was markedly lower at 284 and 318 pM respectively. By contrast the Km values for malonyl-CoA in the normal and the two abnormal reactions were essentially the same (40 - 43 pM), indicating that the affinity of 6-hydroxymellein... 

The structure (101), proposed by King and Morgan in 1960 for the abnormal acetylation product of katonic acid (102), has been confirmed by an X-ray analysis which clearly demonstrates the twisted nature of the 12,13-double bond. The o.r.d. curve of (101) has a molecular amplitude (AO) of 222 000, the largest value reported for a A -ketone. 

W -Acetylkynurenine (i.e., acetylated on the aliphatic amino group) was isolated from a Neurospora mutant culture (970) and was also found in the urine of pyridoxine-deficient rats together with the analogous iV -acetylhy-droxykynurenine (171). It is possible, though there is no direct evidence, that these Af -acetyl derivatives play some part in normal tryptophan metabolism in the rat (c/. 170, 173), or they may, as is probably the case in Neurospora, merely be products of side reactions occurring in the presence of abnormal amounts of kynurenine and hydroxykynurenine. Hydroxykynurenine is also excreted by the pyridoxine-deficient rat as its 0-sulfate... 

Nervous system abnormalities may be attributed in part to diminished synthesis of neurotransmitters rather than to inadequate synthesis of ATP. In pyruvate dehydrogenase complex deficiency, diminished levels of acetyl-CoA cause decreased production of acetylcholine in pyruvate carboxylase deficiency, decreased production of... 

Spectrum of consequences of defects in fatty acid oxidation. The primary effect is inadequate production of acetyl-CoA, which leads to decreased flux through the TCA cycle and lack of ketone body synthesis in the liver. Both of these events cause energy deficits and changes in metabolic regulatory processes. Alterations in hepatic metabolism lead to hypoglycemia and hyperammonemia. Abnormalities also occur in skeletal and cardiac muscle and in the central nervous system. 

In individuals with a deficiency in methylacetoacetyl CoA thiolase (MACT), the conversion of 2-methylacetoacetyl-CoA into acetyl-CoA and propionyl-CoA is inhibited and an accumulation of abnormal catabolic products is observed in the urine. Williams etal. have successfully used both ID and 2D H NMR spectroscopy to investigate the urinary metabolites of two unrelated patients with this disorder. The urine spectra from both patients clearly showed the presence of both 2-methyl-3-hydroxybutyrate and tiglylglycine, which is characteristic for MACT deficiency due to the build-up of metabolites close to the position of enzyme deficiency. However, at 360 MHz, the H NMR spectra are quite crowded and difficult to interpret fully. This difficulty was overcome by the use of the 2D JRES H NMR experiment, which resolved all the proton-proton couplings into the second dimension, allowing much clearer spectral interpretation. In addition to the spin-echo and 2D H J-resolved NMR spectra, 2D H COSY NMR spectroscopy was used to determine the spin-spin coupling connectivities between the protons in the various urinary components. 

To prevent the formation of abnormal Claisen product, Kishi et al. demonstrated trapping the resulting phenolic hydroxyl group by acetylation by carrying out the reaction in acetic anhydride in the presence of potassium or sodium acetate under thermal conditions [42]. For example, 3-methyl-2-butenyl 1-naphthyl ether 44 was... 

A deficiency in pantothenic acid causes the yeast to accumulate acetic acid but it has not been proven that the (unauthorized) addition of pantothenic acid to a fermenting must lowers the wine s volatile acidity originating from yeast. The production by yeasts of abnormally high levels of volatile acidity is probably due to the must s deficiencies in certain lipids. These deficiencies are most likely linked to deficiencies in pantothenic acid, which is involved in the formation of acetyl coenzyme A, responsible for fatty acid and lipid synthesis. 

---