Brain Krebs cycle

NADH, which enters the Krebs cycle. However, during cerebral ischaemia, metabolism becomes anaerobic, which results in a precipitous decrease in tissue pH to below 6.2 (Smith etal., 1986 Vonhanweh etal., 1986). Tissue acidosis can now promote iron-catalysed free-radical reactions via the decompartmentalization of protein-bound iron (Rehncrona etal., 1989). Superoxide anion radical also has the ability to increase the low molecular weight iron pool by releasing iron from ferritin reductively (Thomas etal., 1985). Low molecular weight iron species have been detected in the brain in response to cardiac arrest. The increase in iron coincided with an increase in malondialdehyde (MDA) and conjugated dienes during the recirculation period (Krause et al., 1985 Nayini et al., 1985). 

Acyl coenzyme As are introduced into mitochondria following coenzyme A esterification in the cytoplasm. Mitochondrial entry depends upon a double membrane transport involving carnitine acyltransferases II and I. Excess acetyl CoA is used for KB synthesis. KBs are transported in the blood and ultimately metabolized via the Krebs cycle. KBs are necessary to provide energy to the brain during fasting, a true alternative substrate to glucose. 

Glutamate is the primary excitatory neurotransmitter in the brain. Glutamate is formed by the Krebs cycle and is found free and stored in vesicles in synaptic terminals. Its release is calcium dependent, and an uptake system exists in presynaptic terminals and in glia to terminate its action after release. It is possible that glia metabolize glutamate to glutamine and return it to the neuron for reuse. An excessive release of glutamate can be lethal to cells in the immediate vicinity. 

Glutamate (Glu) is the most abundant amino acid in the CNS. About 30% of the total Glu acts as the major excitatory neurotransmitter in the brain. Glu is synthesized in the nerve terminals from tw o sources from glucose via the Krebs cycle and from glutamine by the enzyme glutaminase. The production of the neurotransmitter glu is regulated via the enzyme glutaminase. Glu is stored in vesicles and released by a Ca " dependent mechanism. 

The starting material for kotonc body synthesis and catabolism, shown in Figure 4.65, is acctyl-CoA. Ketogenesis occurs in the mitochondria of the liver. Hence, ketone body synthesis is, for acetyl-CoA, an alternate fate to immediate oxidation in the Krebs cycle, Tiais pathway results in the formation of acetoacetate and p-hydroxybutyrate. Both appear in the bloodstream (the latter at higher concentrations) and are taken up by various organs, such as the brain and muscle. Here, they are converted back to acetyKloAand then oxidized in the Krebs cycle. 

FIGURE 4,65 Synthesis, circulation, and de adatiun of ketone bodies. Ketone body metabolism involves synthesis in the mitochondria of the fiver, distribution via the bloodstream, and oxidation by the Krebs cycle in various organs, such as ihe brain and muscle,... 

In conclusion, fatty acid oxidation inhibits glucose oxidation and provides acetyl-CoA to the Krebs cycle it also ensures that any glucose that enters skeletal myocytes is not rapidly oxidized, but is converted into lactate that leaves the cells and is transported in the hlood to hepatocytes and cardiac myocytes. Although this conservation of glucose occurs in skeletal myocytes and other tissues, it does not occur in the brain because fatty acids do not cross the blood-brain barrier. Thus even after 2 days of starvation, the brain continues to use -120 g of glucose per day. 

After several days of starvation, the rate of fatty acid release from adipose tissue reaches its maximum. Tissues such as muscle and liver oxidize fatty acids and produce ATP, but its rate of production may not change or it can become lower as a consequence of increased efficiency in starvation. Therefore the fatty acid concentration in the blood rises as the rate of release of fatty acids from adipose tissue exceeds that of tissue usage. In contrast to other tissues, the hver continues to perform (3-oxidation even if the resulting acetyl-CoA is not consumed by the Krebs cycle. It is this feature of its metabolism that gives rise to the production of ketone bodies which serve as an alternative fuel for the brain and other tissues. 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

Perhaps the most likely mechanism of low thiamine-induced brain injury has revolved around impairment of the Krebs cycle and deficit in available ATP (Desjardins and Butterworth, 2005). This could readily lead to apoptosis and necrosis of neurons, as has been described in such patients (Vorhees et al, 1977). In this context, the data on pyruvate dehydrogenase are somewhat difficult to interpret. Postmortem brain from patients with Wernicke s encephalopathy did show a major decrease in pyruvate dehydrogenase, albeit in only a few specimens (Butterworth et al, 1993). However, this was not corroborated in experimental models of this syndrome (Desjardins and Butterworth, 2005 Butterworth et al., 1993). By contrast a major decrease in brain a-ketoglutarate dehydrogenase was seen in every type of thiamine deficiency (Desjardins and Butterworth, 2005 Butterworth et al., 1993). Moreover, an impairment in this enzyme could readily explain an increase in brain lactate, due to anaerobic metabolism, and this has been observed uniformly, even... 

Clarke D D, London J, and Garfmkel D (1978) Computer Modeling as an Aid to Understanding Metabolic Compartmentation of the Krebs Cycle m Brain Tissue, in Amino Acids as Chemical Transmitters (Fonnum F , ed.), pp. 725-738, Plenum, New York... 

Krebs cycle has different functions in different tissues. For example, in muscle and brain it oxidises acetyl CoA to form NADH and FADH2, which are used to generate ATP in the respiratory chain (Chapters 11-13). In liver, during fasting, acetyl CoA is not oxidised by Krebs cycle. Instead, sections of Krebs cycle operate to direct amino acid derivatives towards malate for gluconeogenesis (Chapter 46). In liver and adipose tissue, after feeding, the destiny of acetyl CoA is a brief sojourn in Krebs cycle by incorporation into citrate before export to the cytosol for biosynthesis to fatty acids (Chapter 21). 

Pyruvic decarboxylase controls the entry of the end products of glycolysis into the Krebs cycle. Therefore, thiamine deficiency must have dramatic consequences if no alternative pathway is available for pyruvic acid oxidation. Understandably, in the absence of an alternative pathway, thiamine deficiency leads to a block of pyruvic decarboxylation, which is the first of the two reactions of the Krebs cycle requiring thiamine. In addition, half of the thiamine content of the brain is used in that reaction. The maintenance of the integrity of the Krebs cycle is probably more important to the cell than that of the hexose monophosphate shunt. 

Thiamine is a cofactor for some important enzymes that participate in the Krebs cycle and the pentose phosphate pathway. Thiamine deficiency may induce damage in regions of the brain with high metabolic demands. Thiamine is also involved in the synthesis of neurotransmittors. In adults, thiamine deficiency may lead to Wernicke s encephalopathy. 

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