a-ketoisocaproic Citrate CO2 acid
^ Branched chain
Isocitrate ketoacid ^ dehydrogenase a-ketoglutarate
a-ketoglutarate dehydrogenase complex
where it enters the tricarboxylic acid cycle. Acetyl-CoA is a key source of energy for mitochondrial oxidation and the production of adenosine tripho-sphate (ATP) as well as an important precursor in lipid metabolism. The impaired functioning of pyru-vate dehydrogenase leads to a lactic acidosis, with increased concentrations of serum pyruvate and/or lactate especially as a result of exercise. The lactate acidosis can be explained by the fact that ATP depletion stimulates glycolysis, thus generating more pyr-uvate. As pyruvate concentrations increase, lactate dehydrogenase converts some of the pyruvate to lac-tate, producing the lactic acidosis. The increases in these compounds formed the basis of the earliest biochemical test for thiamin deficiency, which was later made more reproducible by taking the blood soon after moderate exercise (e.g., climbing a few steps).
Many features of beriberi indicate that thiamin plays an important role in neural tissues. TTP is specifically found in nervous tissues, but although this triphosphorylated metabolite of thiamin has been known for approximately 30 years, its precise role is still in doubt. TDP in the dehydrogenase complexes is undoubtedly also required for normal function. Some of the earliest biochemical studies on the brain documented abnormalities in the oxidative metabolism of glucose and a disruption in energy supply may underlie many of the neurochemical changes and structural lesions associated with thia-min deficiency. For example, acetyl-CoA produced by pyruvate dehydrogenase is a precursor of the parasympathetic transmitter molecule acetylcholine, but the obligatory requirement of glucose as an energy source for nervous tissue indicates the essentiality of TDP. Likewise, the cytosolic enzyme trans-ketolase is also present in nervous tissue, and as a key enzyme in the HMS it may be important in minimizing oxidant stress. The HMS generates NADPH, which is required to maintain glutathione in the reduced state.
The cellular and subcellular localization of the enzymes responsible for metabolism of thiamin phosphates in nervous tissues may indicate possible sites of action of the specific metabolites. Thiamin that enters the brain is phosphorylated by thiamin pyrophosphokinase to form TDP. The concentration of thiamin phosphates is 3 or 4 times higher in neurons than in neuroglia, and the activity of thia-min diphosphatase (TDPase), which converts TDP to TMP, is 20 times higher in neurons than neuro-glia. Thiamin monophosphatase is only detected in neuroglia. Within the neuron, TDPase is mostly localised in the microsomal fraction. Thiamin tri-phosphatase (TTPase), which converts TTP to TDP, is particularly enriched in presynaptic terminals. Stimulation of nerves or treatment with certain neuroactive drugs result in decreases in TDP and particularly TTP in the nerve, with an increase in free TMP in the surrounding fluid. It is postulated that TTP plays an essential role in nerve transmission involving a gating mechanism for sodium and potassium ion transport via the specific ATPase. Some evidence for this comes from patients with Leigh's disease (pathologically similar to Wernicke-Korsakoff syndrome), in whom severe neurological disease is accompanied by a deficiency in TTP but normal TDP concentrations.
The well-documented role of mitochondria in programmed cell death and the importance of thiamin for oxidative metabolism have stimulated investigators to examine brain thiamin homeostasis in neurodegenerative diseases. Diminished thiamin-dependent processes, abnormal metabolism, and oxidative stress accompany the neurodegeneration of Alzheimer's disease (AD), Huntington's disease, Wernicke-Korsakoff syndrome, progressive supra-nuclear palsy, and the adult-onset neurodegenerative diseases that are caused by genes containing variable numbers of CAG repeats within their coding regions. Abnormalities in the thiamin-dependent processes have also been linked with thiamin-responsive maple syrup urine disease, Leigh's disease (a subacute necrotizing encephalomyelopathy), sudden infant death syndrome, cerebellar degeneration, thiamin-responsive anemia, ataxia, and disorders of energy metabolism including pyruvate dehydro-genase deficiency. The extent to which disturbances in thiamin metabolism are a cause or a consequence of the disease process is still under examination.
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