Citric acid cycle precursors

Glycolysis and the citric acid cycle (to be discussed in Chapter 20) are coupled via phosphofructokinase, because citrate, an intermediate in the citric acid cycle, is an allosteric inhibitor of phosphofructokinase. When the citric acid cycle reaches saturation, glycolysis (which feeds the citric acid cycle under aerobic conditions) slows down. The citric acid cycle directs electrons into the electron transport chain (for the purpose of ATP synthesis in oxidative phosphorylation) and also provides precursor molecules for biosynthetic pathways. Inhibition of glycolysis by citrate ensures that glucose will not be committed to these activities if the citric acid cycle is already saturated. 

And so it happened that the detection of isotopic carbon from UC02 in the [i carboxyl group of a-ketoglutarate was celebrated as a discovery of CO 2 fixation in animal tissues, and was taken as evidence that there wasn t any citric acid in the citric acid cycle. A citric acid precursor of a-ketoglutarate would have to be labelled as in compound 1... 

Note All these amino acids are precursors of blood glucose or liver glycogen, because they can be converted to pyruvate or citric acid cycle intermediates. Of the 20 common amino acids, only leucine and lysine are unable to furnish carbon for net glucose synthesis. These amino acids are also ketogenic (see Fig. 18-21). 

As noted earlier, although the citric acid cycle is central to energy-yielding metabolism its role is not limited to energy conservation. Four- and five-carbon intermediates of the cycle serve as precursors for a wide variety of products. To replace intermediates removed for this purpose, cells employ anaplerotic (replenishing) reactions, which are described below. 

As intermediates of the citric acid cycle are removed to serve as biosynthetic precursors, they are replenished by anaplerotic reactions (Fig. 16-15 Table 16-2). Under normal circumstances, the reactions by which cycle intermediates are siphoned off into other pathways and those by which they are replenished are in dynamic balance, so that the concentrations of the citric acid cycle intermediates remain almost constant. 

FIGURE 16-14 Biosynthetic precursors produced by an incomplete citric acid cycle in anaerobic bacteria. These anaerobes lack a-ketoglutarate dehydrogenase and therefore cannot carry out the complete citric acid cycle. a-Ketoglutarate and succinyl-CoA serve as precursors in a variety of biosynthetic pathways. (See Fig. 16-13 for the "normal" direction of these reactions in the citric acid cycle.)... 

Intermediates of the citric acid cycle are drawn off as precursors in many biosynthetic pathways. Shown in red are four anaplerotic reactions that replenish depleted cycle intermediates (see Table 16-2). 

FIGURE 22-9 Overview of amino acid biosynthesis. The carbon skeleton precursors derive from three sources glycolysis (pink), the citric acid cycle (blue), and the pentose phosphate pathway (purple). 

Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. They include all the intermediates of glycolysis and the citric acid cycle. Glycerol, lactate, and the o-keto acids obtained form the deamination of glucogenic amino acids are the most important gluconeogenic precursors. 

The primary substrate of the citric acid cycle is acetyl-CoA. Despite many references in the biochemical literature to substrates "entering" the cycle as oxaloacetate (or as one of the immediate precursors succinate, fumarate, or malate), these compounds are not consumed by the cycle but are completely regenerated hence the term regenerating substrate, which can be applied to any of these four substances. A prerequisite for the operation of a catalytic cycle is that a regenerating substrate be readily available and that its concentration... 

Two molecules of C02 now have been produced and the remaining part of the citric acid cycle is concerned with regeneration of the CoA for forming acetyl CoA from 2-oxopropanoate, and also with regenerating the 2-oxobutanedioate, which is the precursor of citrate. The steps involved are... 

Several of the B vitamins function as coenzymes or as precursors of coenzymes some of these have been mentioned previously. Nicotinamide adenine dinucleotide (NAD) which, in conjunction with the enzyme alcohol dehydrogenase, oxidizes ethanol to ethanal (Section 15-6C), also is the oxidant in the citric acid cycle (Section 20-10B). The precursor to NAD is the B vitamin, niacin or nicotinic acid (Section 23-2). Riboflavin (vitamin B2) is a precursor of flavin adenine nucleotide FAD, a coenzyme in redox processes rather like NAD (Section 15-6C). Another example of a coenzyme is pyri-doxal (vitamin B6), mentioned in connection with the deamination and decarboxylation of amino acids (Section 25-5C). Yet another is coenzyme A (CoASH), which is essential for metabolism and biosynthesis (Sections 18-8F, 20-10B, and 30-5A). 

Coenzymes can be either inorganic species such as coenzyme F450 and or purely organic as in coenzyme A (2.7), the coenzyme that carries acyl groups in the synthesis and oxidation of fatty acids, and is responsible for oxidation of pyruvate in the citric acid cycle. Vitamins are commonly coenzymes or their precursors. Coenzyme A is vitamin B5 and we will look in detail at cobalamin, vitamin B12, by way of an example in the next section. Some examples of vitamin and non-vitamin coenzymes are shown in Table 2.3. 

Oxaloacetate, the product of the pyruvate carboxylase reaction, functions both as an important citric acid cycle intermediate in the oxidation of acetyl CoA and as a precursor for gluconeogenesis. The activity of pyruvate carboxylase depends on the presence of acetyl CoA so that more oxaloacetate is made when acetyl CoA levels rise. 

The citric acid cycle, also known as the TCA (tricarboxylic acid) cycle or Krebs cycle (after its discoverer in 1937), is used to oxidize the pyruvate formed during the glycolytic breakdown of glucose into C02 and H20. It also oxidizes acetyl CoA arising from fatty acid degradation (Topic K2), and amino acid degradation products (Topic M2). In addition, the cycle provides precursors for many biosynthetic pathways. 

---