Pathways of Pyruvate Metabolism

Whether carbohydrate is metabolized by the EMP pathway or the HMS pathway, pyruvic acid is the common end-product. Pyruvate may be 

Carbohydrates are important in the nutrition of all people and nearly all domestic animals. The edible carbohydrates and fats provide approximately 90% of the calories in the diet of North Americans (Jf), and a large but variable percentage is furnished by the carbohydrates. No doubt a large portion of all the food energy ever used by humans was derived from starches and sugars, the major carbohydrates in nutrition. 

Some of the information concerning the role of carbohydrates in nutri- 

Recommended Dietary Allowances, Publ. 302, revised. National Research Council, Washington, D. C., 1953. 

In general all carbohydrates must be converted to their constituent monosaccharides before they can be absorbed by the gastrointestinal tract. The digestive processes are largely dependent on the action of suitable enzymes. However, the acidity of the stomach may be great enough at times to cause the nonenzymatic hydrolysis of sucrose, and probably some other disaccharides. 

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Figure 13.3 Alternative pathways of pyruvate metabolism by homofer-mentative lactic streptococci. CoA = coenzyme A TPP = thiamine pyrophosphate. (Adapted from Thomas et at. 1979.)...

Major pathways of pyruvate metabolism. Pyruvate is metabolized through four major enzyme pathways Lactate dehydrogenase (LDH), pyruvate dehydrogenase complex (PDH), pyruvate carboxylase (PC), and alanine aminotransferase (ALT). Arrows indicate multiple steps. 

In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate (Fig. 18-25). Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name phenylketonuria. Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. 

Most known thiamin diphosphate-dependent reactions (Table 14-2) can be derived from the five halfreactions, a through e, shown in Fig. 14-3. Each halfreaction is an a cleavage which leads to a thiamin- bound enamine (center, Fig. 14-3) The decarboxylation of an a-oxo acid to an aldehyde is represented by step b followed by a in reverse. The most studied enzyme catalyzing a reaction of this type is yeast pyruvate decarboxylase, an enzyme essential to alcoholic fermentation (Fig. 10-3). There are two 250-kDa isoenzyme forms, one an a4 tetramer and one with an ( P)2 quaternary structure. The isolation of ohydroxyethylthiamin diphosphate from reaction mixtures of this enzyme with pyruvate52 provided important verification of the mechanisms of Eqs. 14-14,14-15. Other decarboxylases produce aldehydes in specialized metabolic pathways indolepyruvate decarboxylase126 in the biosynthesis of the plant hormone indoIe-3-acetate and ben-zoylformate decarboxylase in the mandelate pathway of bacterial metabolism (Chapter 25).1243/127... 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

Figure 7-1. Pathways of fuel metabolism and oxidative phosphorylation. Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis, or for oxidation to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Long-chain fatty acids are transported into mitochondria, where they undergo [ -oxidation to ketone bodies (liver) or to acetyl-CoA (liver and other tissues). Reducing equivalents (NADH, FADII2) are generated by reactions catalyzed by the PDC and the tricarboxylic acid (TCA) cycle and donate electrons (e ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (Complex 0 or at succinate ubiquinone oxidoreductase (Complex ID- Cytochrome c oxidase (Complex IV) catalyzes the reduction of molecular oxygen to water, and ATP synthase (Complex V) generates ATP fromADP Reprinted with permission from Stacpoole et al. (1997).

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Fig. 2.1 Schematic pathway of heterofermentative metabolism. Intermediate and final glucose metabolism products are indicated by arrows. Catalytic enzymes are abbreviated in bold (LDH lactate dehydrogenase PDH pyruvate dehydrogenase PFL pyruvate-formate lyase a-ALS ace-tolactate synthase) (Miyoshi et al. 2003)...

Fig. 1. Pathways of glucose metabolism in eubacteria and eukaryotes. The three major catabolic pathways are the Embden-Meyerhof glycolytic sequence (solid lines), the Entner-Doudoroff pathway (heavy solid lines) and the pentose phosphate pathway (dashed lines). The sequence from glyceraldehyde 3-phosphate to pyruvate is common to all three pathways.

Diacetyl can be produced by either homolactic or heterolactic pathways of sugar metabolism (via free pyruvate) or by utilization of citric acid (see Figs. 1-1 lA and 1-1 IB). In this case, citric acid is first converted to oxaloacetic and acetic acids. The former is then decarboxylated to pyruvate which undergoes a second decarboxylation and condensation with thiamine pyrophosphate (TPP) to yield active acetaldhyde, which reacts with another pyruvate to yield a-acetolactate which undergoes oxidative decarboxylation to yield diacetyl and its equilibrium products see Fig. 1-11 A. In the case of other LAB, the precursor, a-acetolactate is not produced. Here active acetaldehyde, produced as described above, reacts with acetyl CoA to yield diacetyl see Fig. 1-1 IB. 

The amount of pyruvate dissimilated in diabetic muscle is smaller than that in normal muscle, but pyruvate dissimilation can be normalized by the addition of insulin in vitro. This suggests that there is more than one metabolic defect in diabetes, and that in addition to interference with glucose usage, a block in the oxidation pathway of pyruvate may also exist. 

Attempts to provide further evidence on the role of insulin on the hexokinase reaction include studies on insulin s effect on certain pathways of carbohydrate metabolism that bypass the hexokinase reaction. For example (1) absence of an effect of insulin on the usage of a sugar such as fructose, which is metabolized after phosphorylation by enzymes other than hexokinase (2) the fact that fructose oxidation is unaltered in alloxan-diabetic animals and (3) the effect of insulin on glycogen biosynthesis in diaphragm or liver slices from [ " Qglucose and labeled pyruvate. 

Diacetyl may be synthesized by either homolactic or heterolactic pathways of sugar metabolism as well as by utilization of citric acid (Fig. 2.9). Citric acid is hrst converted to acetic acid and oxaloacetate the latter is then decarboxylated to pyruvate. Although earlier reports indicated that diacetyl synthesis by lactic acid bacteria does not proceed via a-acetolactate (Gottschalk, 1986), more recent evidence suggests that this pathway is active in lactic acid bacteria (Ramos et al., 1995). Here, pyruvate undergoes a second decarboxylation and condensation with thiamine pyrophosphate (TPP) to yield active acetaldehyde. This compound then reacts with another molecule of pyruvate to yield a-acetolactate, which, in... 

Loss of sulfur by desulfhydrase activity, which is generally now considered to be of little or no metabolic significance, leads to the formation of pyruvate. More important, the pathway of oxidation of the sulfur of cysteine (see Chapter 16) also results in the formation of pyruvate. The subsequent metabolism of pyruvic acid should then be along the well-known pathways of carbohydrate metabolism. 

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