Succinyl-CoA synthesis

In experimental animals, deficiency of pantothenic acid (needed for CoASH and, hence, succinyl-CoA synthesis), lack of vitamin Be, or the presence of compounds that block the functioning of pyridoxal phosphate (e.g.. 

A fourth reaction for succinyl-CoA synthesis is via a CoA transferase from acetoacetyl-CoA to succinate. This enzyme has a low activity in fiver but is present in muscle and kidney. 

The exact mechanism of action of the -amino levulinic acid synthetase is not clear. It involves the activation of glycine by pyridoxal phosphate in a Schiff base formation on the enzyme. A proton is lost in the process, and a stable carbanion is formed. In the presence of succinyl CoA, the activated glycine is transferred to succinate, but it is not clear whether the decarboxylation occurs while the succinate and glycine are still attached to the enzyme or later. The activity of the -amino levulinic acid synthetase is inhibited by L-penicillamine, thiosolidine, and L-cysteine. The compounds presumably react with pyridoxal phosphate forming a thiazolidine ring. The enzyme molecule is itself inhibited by the addition of para-chloro-mercuri-benzoic acid. Insofar as succinate is a precursor of 5-amino levulinic acid, the pathway for succinyl CoA synthesis acquires particular significance (refer to the first part of this book). In the reticulocyte, the tricar-... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

FIGURE 2.1.3 Synthesis of 5-aminolevulinic acid (ALA) by the C-5 pathway (from a-ketoglutarate or glutamate) and the C-4 pathway (condensation of succinyl CoA with glycine). 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

Fig. 1. The metabolic cycle for the synthesis and degradation of poly(3HB). (1) 3-ketothiolase (2) NADPH-dependent acetoacetyl-CoA reductase (3) poly(3HB) synthase (4) NADH-dependent acetoacetyl-CoA reductase (5), (6) enolases (7) depolymerase (8) d-(-)-3-hydroxybutyrate dehydrogenase (9) acetoacetyl-CoA synthetase (10) succinyl-CoA transferase (11) citrate synthase (12) see Sect. 3...

We should note at this point that the TCA cycle is more than just a means of producing NADH for oxidative phosphorylation. The pathway also provides a number of useful intermediates for other, often synthetic, pathways. For example, citrate is the starting substance for fat synthesis (Chapter 9) succinyl-CoA is required for haem production and 2-oxoglutarate and oxaloacetate in particular are involved with amino acid and pyrimidine metabolism. Pathways which have dual catabolic/anabolic functions are referred to as amphibolic . 

In addition to their well known role in protein structure, amino acids also act as precursors to a number of other important biological molecules. For example, the synthesis of haem (see also Section 5.3.1), which occurs in, among other tissues, the liver begins with glycine and succinyl-CoA. The amino acid tyrosine which maybe produced in the liver from metabolism of phenylalanine is the precursor of thyroid hormones, melanin, adrenaline (epinephrine), noradrenaline (norepinephrine) and dopamine. The biosynthesis of some of these signalling molecules is described in Section 4.4. 

The product succinyl-CoA is able to participate in ATP synthesis as an example of substrate-level phosphorylation - we met some other examples in the glycolytic pathway. Essentially, hydrolysis of succinyl-CoA liberates snfficient energy that it can be coupled to the synthesis of ATP from ADP. However, guanosine triphosphate (GTP) is the... 

Succinyl CoA (upper left), an intermediate in the tricarboxylic acid cycle, undergoes condensation with glycine and subsequent decarboxylation to yield 5-aminolevulinate (ALA). The ALA synthase responsible for this step is the key enzyme of the whole pathway. Synthesis of ALA synthase is repressed and existing enzyme is inhibited by heme, the end product of the pathway. This is a typical example of end-product or feedback inhibition. 

Eugene Kennedy and Albert Lehninger showed in 1948 that, in eulcaiyotes, the entire set of reactions of the citric acid cycle takes place in mitochondria. Isolated mitochondria were found to contain not only all the enzymes and coenzymes required for the citric acid cycle, but also all the enzymes and proteins necessaiy for the last stage of respiration—electron transfer and ATP synthesis by oxidative phosphoiylation. As we shall see in later chapters, mitochondria also contain the enzymes for the oxidation of fatty acids and some amino acids to acetyl-CoA, and the oxidative degradation of other amino acids to a-ketoglutarate, succinyl-CoA, or oxaloacetate. Thus, in nonphotosynthetic eulcaiyotes, the mitochondrion is the site of most energy-yielding... 

Conversion of Succinyl-CoA to Succinate Succinyl-CoA, like acetyl-CoA, has a thioester bond with a strongly negative standard free energy of hydrolysis (AG ° = -36 kJ/mol). In the next step of the citric acid cycle, energy released in the breakage of this bond is used to drive the synthesis of a phosphoanhydride bond in either GTP or ATP, with a net AG ° of only -2.9 kJ/mol. Succinate is formed in the process ... 

The formation of ATP (or GTP) at the expense of the energy released by the oxidative decarboxylation of a-ketoglutarate is a substrate-level phosphorylation, like the synthesis of ATP in the glycolytic reactions catalyzed by glyceraldehyde 3-phosphate dehydrogenase and pyruvate kinase (see Fig. 14-2). The GTP formed by succinyl-CoA synthetase can donate its terminal phosphoryl group to ADP to form ATP, in a reversible reaction catalyzed by nucleoside diphosphate kinase (p. 505) ... 

The pathways for degradation of pyrimidines generally lead to NH4 production and thus to urea synthesis. Thymine, for example, is degraded to methyl-malonylsemialdehyde (Fig. 22-46), an intermediate of valine catabolism. It is further degraded through propionyl-CoA and methylmalonyl-CoA to succinyl-CoA (see Fig. 18-27). 

The condensation of acetyl CoA and oxaloacetate to form citrate is catalyzed by citrate synthase (Figure 9.5). This aldol condensation has an equilibrium far in the direction of citrate synthesis. Citrate synthase is allosterically activated by Ca2+ and ADP, and inhibited by ATP, NADH, succinyl CoA, and fatty acyl CoA derivatives (see Figure 9.9). However, the primary mode of regulation is also deter mined by the availability of its substrates, acetyl CoA and oxaloac etate. [Note Citrate, in addition to being an intermediate in the TCA cycle, provides a source of acetyl CoA for the cytosolic synthesis of... 

Tissues that synthesize heme, and the sources of porphyrin s carbon and nitrogen The major sites of heme biosynthesis are the liver (where the rate of synthesis is highly variable) and the erythrocyte-producing cells of the bone marrow (where the rate is generally constant). All the carbon and nitrogen atoms are provided by glycine and succinyl CoA. 

The following problem in energy transfer arises occasionally A thioester, such as succinyl-CoA, is available to a cell and the energy available in its unstable linkage is needed for synthesis of a different thioester. It would be possible for a cell to first form ATP or GTP,... 

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