These reactions have different functions in cells. The reaction involving acetyl-CoA and butyrate (EC2.8.3.8), for example, forms butyrate during fermentation.[3] The reaction involving acetyl-CoA and succinate (EC2.8.3.18) is part of a modified TCA cycle[4] or forms acetate during fermentation.[5] The reaction involving acetoacetate-CoA and succinate (EC2.8.3.5) degrades the ketone body acetoacetate formed during ketogenesis.[6]
Many enzymes can catalyze multiple reactions, whereas some enzymes are specific and catalyze only one.[1]
Families
The CoA-transferases have been divided into six families (Cat1, OXCT1, Gct, MdcA, Frc, CitF) based on their amino acid sequences and reactions catalyzed.[1] They also differ in the type of catalysis and their crystal structures. Despite some shared properties, these six families are not closely related (<25% amino acid similarity).
Three families catalyze CoA-transferase reactions almost exclusively. The Cat1 family catalyzes reactions involving small acyl-CoA, such as acetyl-CoA (EC2.8.3.18)), propionyl-CoA (EC2.8.3.1,EC2.8.3.12), and butyryl-CoA (EC2.8.3.8). The OXCT1 family uses oxo (EC2.8.3.5,EC2.8.3.6) and hydroxy acyl-CoA (EC2.8.3.6,EC2.8.3.1). The Frc family uses unusual acyl-CoA, including CoA thioesters of oxalate (EC2.8.3.16,EC2.8.3.19), bile acids (EC2.8.3.25), and aromatic compounds (EC2.8.3.15,(EC2.8.3.17). Two families catalyze CoA-transferase reactions, but they also catalyze other transferase reactions. The CitF family catalyzes reactions involving acetyl-CoA and citrate EC2.8.3.10), but its main role is as an acyl-ACP transferase (as part of citrate lyase; EC4.1.3.6). The MdcA family catalyzes reactions involving acetyl-CoA and malonate (EC2.8.3.3), but it too is an acyl-ACP transferase (as part of malonate decarboxylase; EC4.1.1.9).
The Gct family has members that catalyze CoA-transferase reactions, but half of the members do not. They instead catalyze hydrolysis or other reactions involving acyl-CoA.
Historically, the CoA-transferases were divided three families (I, II, III).[2] However, members of families I (Cat1, OXCT1, Gct) are not closely related, and the family is not monophyletic.[1] Members of family II (CitF, MdcA) are also not closely related.[1]
Types of catalysis
Most CoA transferases rely on covalent catalysis to carry out reactions. The reaction starts when an acyl-CoA (the CoA donor) enters the active site of the enzyme.[7] A glutamate in the active site forms an adduct with acyl-CoA. The acyl-CoA breaks at the thioester bond, forming a CoA and carboxylic acid. The carboxylic acid remains bound to the enzyme, but it is soon displaced by CoA and leaves. A new carboxylic acid (the CoA acceptor) enters and forms a new acyl-CoA. The new acyl-CoA is released, completing the transfer of CoA from one molecule to another.
The type of catalysis differs by family.[1] In Cat1, OXCT1, and Gct families, the catalytic residue in the active site is a glutamate. However, the glutamate in the Cat1 family is in a different position than in the OXCT1 and Gct families. In the Frc family, the catalytic residue is an aspartate, not a glutamate. In MdcA and CitF families, covalent catalysis is not thought to occur.
Crystal structures
Crystal structures have been determined for 21 different enzymes.[1] More structures have been determined, but they belong to putative enzymes (proteins with no direct evidence of catalytic activity).
All CoA-transferases have alternating layers of α helices and β sheets, and thus they belong to the α/β class of proteins.[1] The number and arrangement of these layers differs by family. The Gct family, for example, has extra layers of α helices and β sheets compared to Cat1 and OXCT1 families.
Further, all enzymes have two different domains.[1] These domains can either occur on the same polypeptide or can be separated between two different polypeptides. In some cases, the genes for the domains are duplicated in the genome.
Occurrence in organisms
CoA transferases have been found in all three domains of life.[1] The majority have been found in bacteria, with fewer in eukaryotes.[1] One CoA transferase has been found in archaea.[8]
Mutations in two different CoA-transferases have been described and lead to disease in humans. 3-oxoacid CoA-transferase(EC2.8.3.5) uses the ketone body acetoacetate. Mutations in the enzyme cause accumulation of acetoacetate and ketoacidosis. The severity of ketoacidosis depends on the mutation.[6]
The citric acid cycle (CAC)—also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism and may have originated abiogenically. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.
Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it (or a thioester) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate (vitamin B5), and adenosine triphosphate (ATP).
A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups from one molecule to another. They are involved in hundreds of different biochemical pathways throughout biology, and are integral to some of life's most important processes.
In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cycle, and NADH and FADH2, which are co-enzymes used in the electron transport chain. It is named as such because the beta carbon of the fatty acid undergoes oxidation to a carbonyl group. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.
Methylmalonyl CoA epimerase is an enzyme involved in fatty acid catabolism that is encoded in human by the "MCEE" gene located on chromosome 2. It is routinely and incorrectly labeled as "methylmalonyl-CoA racemase". It is not a racemase because the CoA moiety has 5 other stereocenters.
In enzymology, a 3-oxoacid CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a 3-oxoadipate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, an acetate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a malonate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, an oxalate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a propionate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a succinate-citramalate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a succinate-hydroxymethylglutarate CoA-transferase is an enzyme that catalyzes the chemical reaction
In enzymology, a succinate-CoA ligase (ADP-forming) is an enzyme that catalyzes the chemical reaction
The enzyme succinyl-CoA hydrolase (EC 3.1.2.3) catalyzes the reaction
In enzymology, a 3-oxoadipyl-CoA thiolase is an enzyme that catalyzes the chemical reaction
In enzymology, an acetyl-CoA C-acetyltransferase is an enzyme that catalyzes the chemical reaction
3-oxoacid CoA-transferase 1 (OXCT1) is an enzyme that in humans is encoded by the OXCT1 gene. It is also known as succinyl-CoA-3-oxaloacid CoA transferase (SCOT). Mutations in the OXCT1 gene are associated with succinyl-CoA:3-oxoacid CoA transferase deficiency. This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate.
Succinyl-CoA:3-oxoacid CoA transferase deficiency is an inborn error of ketone body utilization. Succinyl-CoA:3-oxoacid CoA transferase catalyzes the transfer of coenzyme A from succinyl-coenzyme A to acetoacetate. It can be caused by mutation in the OXCT1 gene.
↑ Mullins EL, Kappock TJ (2012). "Crystal structures of Acetobacter aceti succinyl-coenzyme A (CoA):acetate CoA-transferase reveal specificity determinants and illustrate the mechanism used by class I CoA-transferases". Biochemistry. 51 (42): 8422–34. doi:10.1021/bi300957f. PMID23030530.
1 2 Marlaire S, Van Schaftingen E, Veiga-da-Cunha M (2014). "C7orf10 encodes succinate-hydroxymethylglutarate CoA-transferase, the enzyme that converts glutarate to glutaryl-CoA". J. Inherit. Metab. Dis. 37 (1): 13–9. doi:10.1007/s10545-013-9632-0. PMID23893049. S2CID2054736.
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