Coenzyme A dithioesters: synthesis, characterization and reaction with citrate synthase and acetyl-CoA:choline

Wlassics, I.; Anderson, Vernon E.

doi:10.1016/0167-4838(88)90126-4

Cited by 18 publications

(18 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comparison of these structures showed that the 2'-OH-of the ribityl side chain of FAD would have to be rotated away from the carbonyl oxygen of the substrate to accommodate the larger sulfur atom. While some enzymes can tolerate such substitution with little effect (Storer & Carey, 1985), replacement of C=O by C=S generally significantly slows catalysis [e.g., Wlassics et al (1988) and Anderson et al (1990)l. Thus, the comparatively weak binding of 2-azadithiooctanoyl-CoA, the low turnover with dithiooctanoyl-CoA, and the molecular modeling results are consistent with a tight interaction between the substrate carbonyl oxygen and its binding pocket in the medium chain dehydrogenase.…”

Section: Discussionmentioning

confidence: 99%

“…The following thioester analogues were synthesized in a range of chain lengths (see Results) and characterized as described previously: 3-thiaacyl- (Lau et al, 1988);3-ketoacyl-(Thorpe, 1986); trans-2-enoyl- (Powell et al, 1987); and 4-thia-iran.s-2-enoyl-CoA (Lau et al, 1989). Octanoyldithio-CoA was synthesized from S-phenyldithiooctanoate and CoA as described by Wlassics et al (1988). S-Phenyldithiooctanoate was prepared from the corresponding thiooctanoate with Lawesson's reagent and was purified by flash chromatography on silica gel.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Role of the Carbonyl Group in Thioester Chain Length Recognition by the Medium Chain Acyl-CoA Dehydrogenase

Trievel¹,

Wang²,

Anderson³

et al. 1995

Biochemistry

Self Cite

View full text Add to dashboard Cite

Medium chain acyl-CoA dehydrogenase from pig kidney catalyzes the oxidation of acyl-CoA thioesters to trans-2-enoyl-CoA derivatives with an optimal chain length of about C-8. The binding energy for alkyl-SCoA thioethers shows no such optimum but increases linearly from C-2 to C-16 with a slope of about 390 cal/-CH2 group. In contrast, four types of CoA-thioester analogues (2-aza-acyl-, 3-thia-acyl-, 3-keto-acyl-, and trans-2-enoyl-) yield an incremental binding energy of about 800 cal/-CH2 group until a chain length of about C-8 is reached. The observed binding energy then decreases, or remains constant, with increasing chain length. Studies with dithiooctanoyl-CoA and 2-azadithiooctanoyl-CoA show that the C = S moiety is accommodated poorly by the medium chain dehydrogenase. A model for chain length discrimination, based on the crystal structure of the enzyme [Kim, J. J. P., Wang, M., & Paschke, R. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 7523-7527], is proposed in which hydrogen-bonding interactions between enzyme and thioester carbonyl oxygen atom are maximized at optimal chain lengths. Oversized chains decrease the frequency of effective alignment between enzyme and the C-1 to C-3 region of thioester ligands. Thus the extent of polarization of bound 4-thia-trans-2-enoyl-CoA thioesters decreases sharply with chains longer than C-12.(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Role of the Carbonyl Group in Thioester Chain Length Recognition by the Medium Chain Acyl-CoA Dehydrogenase

Trievel¹,

Wang²,

Anderson³

et al. 1995

Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…One should stress that in brain mitochondria the rate of acetyl-CoA utilization for citrate synthesis is about two orders of magnitude higher than the rate of its hydrolysis when comparing V max values of citrate synthase and acetyl-CoA hydrolase, respectively ( Table 1 ) ( Wlassics et al, 1988 ; Suematsu and Isohashi, 2006 ). Also, isolated whole brain mitochondria or synaptosomes utilizing pyruvate with malate, accumulated several times greater amounts of citrate than those of acetate ( Łysiak et al, 1976 ).…”

Section: Acetyl-coa Precursors In the Brainmentioning

confidence: 99%

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Ronowska

Szutowicz

Bielarczyk

et al. 2018

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Brain neurons, to support their neurotransmitter functions, require a several times higher supply of glucose than non-excitable cells. Pyruvate, the end product of glycolysis, through pyruvate dehydrogenase complex reaction, is a principal source of acetyl-CoA, which is a direct energy substrate in all brain cells. Several neurodegenerative conditions result in the inhibition of pyruvate dehydrogenase and decrease of acetyl-CoA synthesis in mitochondria. This attenuates metabolic flux through TCA in the mitochondria, yielding energy deficits and inhibition of diverse synthetic acetylation reactions in all neuronal sub-compartments. The acetyl-CoA concentrations in neuronal mitochondrial and cytoplasmic compartments are in the range of 10 and 7 μmol/L, respectively. They appear to be from 2 to 20 times lower than acetyl-CoA Km values for carnitine acetyltransferase, acetyl-CoA carboxylase, aspartate acetyltransferase, choline acetyltransferase, sphingosine kinase 1 acetyltransferase, acetyl-CoA hydrolase, and acetyl-CoA acetyltransferase, respectively. Therefore, alterations in acetyl-CoA levels alone may significantly change the rates of metabolic fluxes through multiple acetylation reactions in brain cells in different physiologic and pathologic conditions. Such substrate-dependent alterations in cytoplasmic, endoplasmic reticulum or nuclear acetylations may directly affect ACh synthesis, protein acetylations, and gene expression. Thereby, acetyl-CoA may regulate the functional and adaptative properties of neuronal and non-neuronal brain cells. The excitotoxicity-evoked intracellular zinc excess hits several intracellular targets, yielding the collapse of energy balance and impairment of the functional and structural integrity of postsynaptic cholinergic neurons. Acute disruption of brain energy homeostasis activates slow accumulation of amyloid-β1-42 (Aβ). Extra and intracellular oligomeric deposits of Aβ affect diverse transporting and signaling pathways in neuronal cells. It may combine with multiple neurotoxic signals, aggravating their detrimental effects on neuronal cells. This review presents evidences that changes of intraneuronal levels and compartmentation of acetyl-CoA may contribute significantly to neurotoxic pathomechanisms of different neurodegenerative brain disorders.

show abstract

“…CoA thioethers, prepared by alkylation of CoA, are potent inhibitors of several enzymes and have been utilized in mechanistic and structural studies of their target enzymes . CoA dithioesters, prepared by acylation of CoA with a phenyl dithioester, have also been studied and though generally less stable than thioesters to nonenzymatic reactions, are resistant or sluggish toward enzyme-catalyzed reactions. , Nonhydrolyzable ketone isosteres, prepared by nonenzymatic , and more recently enzymatic methods have found substantial utility in enzymology. Transition state analog inhibitors of several CoA ester-utilizing enzymes have been prepared.…”

mentioning

confidence: 99%

Coenzyme A Hemithioacetals as Easily Prepared Inhibitors of CoA Ester-Utilizing Enzymes

1996

View full text Add to dashboard Cite

Hemithioacetals are formed by reactions of coenzyme A (CoA) with aldehydes in aqueous solution. Equilibria for hemithioacetal formation with four commercially available aldehydes and rate constants for hemithioacetal dissociation have been studied. The hemithioacetals are viewed as acyl-CoA analogs having a tetrahedral center in place of the planar trigonal thioester carbonyl carbon. These compounds may serve as mimics of the tetrahedral intermediate or transition state in the reactions of acyl-CoA dependent acyltransferase enzymes. The hemithioacetal generated by reaction of CoA with formaldehyde is a poor inhibitor of chloramphenicol acetyltransferase, with a K i more than 6-fold higher than the K m for the substrate acetyl-CoA. The hemithioacetals formed by reaction of CoA with acetaldehyde and trifluroacetaldehyde are substantially better inhibitors, with K i values approximately 2.4-fold and 10-fold lower than the K m values for acetyl-CoA, respectively. The hemithioacetal formed by reaction of CoA with succinic semialdehyde inhibits succinic thiokinase, with a K i 4-fold lower than the K m for the substrate succinyl-CoA. The CoA hemithioacetals provide a novel readily accessible new class of acyl-CoA analogs for use in mechanistic and structural studies of CoA ester-utilizing enzymes.

show abstract

Coenzyme A dithioesters: synthesis, characterization and reaction with citrate synthase and acetyl-CoA:choline

Cited by 18 publications

References 27 publications

Role of the Carbonyl Group in Thioester Chain Length Recognition by the Medium Chain Acyl-CoA Dehydrogenase

Role of the Carbonyl Group in Thioester Chain Length Recognition by the Medium Chain Acyl-CoA Dehydrogenase

The Regulatory Effects of Acetyl-CoA Distribution in the Healthy and Diseased Brain

Coenzyme A Hemithioacetals as Easily Prepared Inhibitors of CoA Ester-Utilizing Enzymes

Contact Info

Product

Resources

About