Pyruvate metabolism

Let s turn now to the fate of pyruvate in aerobic tissues. Pyruvate must first be transported into the mitochondria, where it can then be oxidized to give acetyl CoA, which can then be used to make fat for storage or it can be further oxidized to carbon dioxide via the Kreb s TCA Cycle. 

The oxidation of pyruvate to acetyl CoA is accomplished by the Pyruvate Dehydrogenase complex, a large, multi-component enzyme with three main enzyme subunits. 

The first enzyme of this complex, pyruvate dehydrogenase (note that, unusual for the DH appellation, there is no direct NAD or FAD involvement), catalyzes two sequential reactions. In the first reaction, catalyzed by the subunit of the 

The lipoamide of dihydrolipoyl transacetylase constitutes a long arm which may now move the acetyl group from the active site of pyruvate DH to its own active site where the lipoamide is exchanged for Coenzyme A-SH. (On the mammalian enzyme the 60 subunits of the transacetylase seem to form a pool of lipoyl groups among which the acetyl groups are freely exchanged). 

Note that in the reactions of dihydrolipoyl transacetylase the lipoamide has been reduced from a disulphide to two sulphhydryl groups. In order to continue operation lipoamide must be reoxidized and that is accomplished by the final enzyme of the complex, dihydrolipoyl dehydrogenase. The reactions catalyzed by this enzyme are complex, but the net result is the transfer of two electrons from the lipoamide to NAD+ to give NADH. 

Role of Anaerobic Glycolysis in Various Tissues and Cells 

The only pathway that provides ATP in mature erythrocytes is glycolysis. Because these cells lack mitochondria, a nucleus, and other organelles required for protein synthesis, deficiency of glycolytic enzymes may 

Some enzymopathies of erythrocytes may be associated with multisystem disease (e.g., aldolase deficiency with mental and growth retardation). Individuals with 6-phosphofructokinase deficiency exhibit hemolysis and myopathy and have increased deposition of muscle glycogen (a glycogen storage disease see Chapter 15). The myopathy is usually characterized by muscle weakness and exercise intolerance. (See also Chapters 10, 15, and 28.) 

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. 

Conversion of pyruvate to ethanol by certain yeast strains occurs in two steps. It is first decarboxylated to acetaldehyde by pyruvate decarboxylase, which utilizes thiamine pyrophosphate (TPP) as coenzyme. 

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Inhibition of Pyruvate Metabolism Leads to Lactic Acidosis... 

Bakken, I. J., White, L. R., Aasly, J. etal. Lactate formation from [U-13C] aspartate in cultured astrocytes compartmentation of pyruvate metabolism. Neurosci. Lett. 237 117-120, 1997. 

Defects of substrate utilization. Pyruvate dehydrogenase (PDH) deficiency can cause alterations of pyruvate metabolism, as can defects of pyruvate carboxylase, as discussed earlier. Over 200 patients have been described with a disturbance of the PDH complex (PDHC) [15,16]. The clinical picture includes several phenotypes ranging from a severe, devastating metabolic disease in the neonatal period to a benign, recurrent syndrome in older children. There is considerable overlap clinically and biochemically with other disorders (see below). 

De Meirleir,L. Defects of pyruvate metabolism and the Krebs cycle. /. Child Neurol. 17(Suppl. 3) S26-S33,2002. 

Fructose and mannose metabolism Galactose metabolism Ascorbate and aldarate metabolism Pyruvate metabolism Glyoxylate and dicarboxylate metabolism... 

Lindmark DG, Mtlller M. 1973. Hydrogenosome, a cytoplasmic organelle of the anaerobic flagellate Tritrichomonas foetus, and its role in pyruvate metabolism. J Biol Chem 248 7724-8. 

Vanacova S, Rasoloson D, Razga J, et al. 2001. Iron-induced changes in pyruvate metabolism of Tritrichomonas foetus and involvement of iron in expression of hydrogenosomal proteins. Microbiology 147 53-62. 

Accumulation of metformin can occur in patients with renal insufficiency, and interference with pyruvate metabolism can lead to severe lactic acidosis. Lactic acidosis is more likely in situations associated with anaerobic metabolism, and metformin should not be given to patients with renal disease, liver disease, or severe pulmonary or cardiac disease predisposing to hypoxia. It is recommended to switch patients taking metformin to another oral hypoglycaemic prior to cardiac or other major surgery. 

An unaffected patient will have a negative DNPH result. Mildly affected or partially treated patients may also yield negative results. Patients with a blood phenylalanine level (indicative of PKU) over 1 mmol/1 should generate positive DNPH results. Patients with a blood leucine level (indicative of MSUD) of 0.8 mmol/1 or higher usually show a positive DNPH result. Patients with pyruvate metabolic disorders may also give positive results, as will patients with true and transient disorders of tyrosine degradation. 

Enzymes of pyruvate metabolism (pyruvate dehydrogenase, PDH, or pyruvate carboxylase, PC, defects). 

Fig. 1.4.1 Lactate and pyruvate metabolic pathway. (P Phosphate, PEP phosphoenolpyruvate)...

Steinbiichel A, Muller M (1986) Anaerobic pyruvate metabolism of Tritrichomonas foetus and Trichomonas vaginalis hydrogenosomes. Mol Biochem Parasitol 20 57-65 Sutak R, Dolezal P, Fiumera HL, Hrdy I, Dancis A, Gadillo-Correa M, Johnson PJ, Muller M, Tachezy J (2004) Mitochondrial-type assembly of FeS centers in the hydrogenosomes of the amitochondriate eukaryote Trichomonas vaginalis. Proc Nad Acad Sci USA 101 10368-10373... 

Rotte C, Stejskal F, Zhu G, Keithly JS, Martin W (2001) Pyruvate NADP+ oxidoreductase from the mitochondrion of Euglena gracilis and from the apicomplexan Cryptosporidium parvum a biochemical relic linking pyruvate metabolism in mitochondriate and amitochondriate protists. Mol Biol Evol 18 710-720 Schnarrenberger C, Martin W (2002) Evolution of the enzymes of the citric acid cycle and the glyoxylate cycle of higher plants. A case study of endosymbiotic gene transfer. Eur J Biochem 269 868-883... 

Lavier G (1952) Observation sur les Blastocystis. Ann Parasitol Hum Comp 27 339-356 Lee MJ (1991) Pathogenicity of Blastocystis hominis. J Clin Microbiol 29 2089 Lindmark DG, Muller M (1973) Hydrogenosome, a cytoplasmic organelle of the anaerobic flagellate Tritrichomonas foetus, and its role in pyruvate metabolism. J Biol Chem 248 7724-7728... 

Arch Roum Pathol Exp Microbiol 42 233-242 Steinbuchel A, Muller M (1986) Anaerobic pyruvate metabolism of Tritrichomonas foetus and Trichomonas vaginalis hydrogenosomes. Mol Biochem Prasitol 20 57-65... 

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.)...

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