Ketoglutarate thiamin deficiency

Thiamine deficiency results in early decreases in activity of the mitochondrial enzyme a-ketoglutarate dehydrogenase in brain. Wernicke s encephalopathy, also known as the Wernicke-Korsakoff syndrome is a neuropsychiatric disorder characterized by ophthalmoplegia, ataxia and memory loss. Wernicke s encephalopathy is encountered in chronic alcoholism, in patients with HIV-AIDS and in other disorders associated with grossly impaired nutritional status. The condition results from thiamine deficiency. 

Til. Role of the Vitamin Thiamine People with beriberi, a disease caused by thiamine deficiency, have elevated levels of blood pyruvate and a-ketoglutarate, especially after consuming a meal rich in glucose. How are these effects related to a deficiency of thiamine ... 

Answer Thiamine is required for the synthesis of thiamin pyrophosphate (TPP), a prosthetic group in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes. A thiamin deficiency reduces the activity of these enzyme complexes and causes the observed accumulation of precursors. 

Pekovich SR, Martin PR and Singleton CK (1998) Thiamine deficiency decreases steady-state transketolase and pyruvate dehydrogenase but not alpha-ketoglutarate dehydrogenase mRNA levels in three human cell types. Journal of Nutrition 128, 683-7. 

Many alcoholics such as Al Martini develop thiamine deficiency because alcohol inhibits the transport of thiamine through the intestinal mucosal cells. In the body, thiamine is converted to thiamine pyrophosphate (TPP). TPP acts as a coenzyme in the decarboxylation of a-keto acids such as pyruvate and a-ketoglutarate (see Fig. 8.11) and in the utilization of pentose phosphates in the pentose phosphate pathway. As a result of thiamine deficiency, the oxidation of a-keto acids is impaired. Dysfunction occurs in the central and peripheral nervous system, the cardiovascular system, and other organs. 

In Al Martini s heart failure, which is caused by a dietary deficiency of the vitamin thiamine, pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, and the branched chain a-keto acid dehydrogenase complexes are less functional than normal. Because heart muscle, skeletal muscle, and nervous tissue have a high rate of ATP production from the NADH produced by the oxidation of pyruvate to acetyl CoA and of acetyl CoA to COj in the TCA cycle, these tissues present with the most obvious signs of thiamine deficiency. 

Shi, Q., et al., 2007. Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability. Neurochem Int. 50, 921-931. 

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... 

The changes in a-ketoglutarate decarboxylase and pyruvic acid decarboxylase activities are not the only biochemical alterations observed in thiamine deficiency. The activities of some other enzymes were found to be altered, for example, erythrocyte transke-tolase and adenosine-5 -phosphatase activities are decreased in chicken brain. 

An explanation for the pathogenesis of the lesions observed in thiamine deficiency would seem to follow logically from these biochemical observations, for in the thiamine-deficient animal, at least two enzymes involved in the Krebs cycle are blocked. The block of pyruvic decarboxylase prevents the entry of the products of glycolysis into the Krebs cycle. The block of a-ketoglutarate decarboxylase restricts the oxidation of both carbohydrates and fatty acids. A severe metabolic distortion follows, and one of the main manifestations of the distortion is a reduction of the amount of chemical energy available in the form of ATP. Clearly, those organs that suffer the most from such alterations are those that are metabolically most active, and the heart and the peripheral nervous system surely qualify as such. 

An example of the difficulties encountered in evaluating the role of a vitamin deficiency is provided by those cases in which thiamine deficiency and type I hyperoxaluria are combined. Type I hyperoxaluria is caused by a deficiency in a-ketoglutarate glyoxylate carboxyligase thiamine acts as a cofactor in the reaction and one would expect, therefore, that thiamine deficiency would enhance the severity of the disease. Yet, in patients with Wernicke encephalopathy and... 

Altered activity of a-ketoglutarate dehydrogenase complex (ICGDHC), a key enzyme of the tricarboxylic acid cycle, is a major contributor to damage resulting from thiamine deficiency. 

The function of thiamine (as the pyrophosphate) in Tetrahymena has been suggested as the cocarboxylase of pyruvate, as pyruvic acid accumulates in thiamine-deficient cultures. Other organic acids also accumulate in such cultures, one of which is a-ketoglutaric acid. It appears likely that thiamine (along with thioctic acid, see below) functions in the decarboxylation of a-ketoglutaric acid in the same manner as it does with pyruvic. The mediation of pyruvic decarboxylation by thiamine has long been known in birds and mammals, so it is altogether expected that the same function would be found in the ciliates. 

In thiamin deficiency, pyruvic and alpha-ketoglutaric acids tend to accumulate in the body sometimes they are measured as a means of determining thiamin status. 

Beriberi is caused by a deficiency of thiamin (also called thiamine, aneurin(e), and vitamin Bj). Classic overt thiamin deficiency causes cardiovascular, cerebral, and peripheral neurological impairment and lactic acidosis. The disease emerged in epidemic proportions at the end of the nineteenth century in Asian and Southeast Asian countries. Its appearance coincided with the introduction of the roller mills that enabled white rice to be produced at a price that poor people could afford. Unfortunately, milled rice is particularly poor in thiamin thus, for people for whom food was almost entirely rice, there was a high risk of deficiency and mortality from beriberi. Outbreaks of acute cardiac beriberi still occur, but usually among people who live under restricted conditions. The major concern today is subclinical deficiencies in patients with trauma or among the elderly. There is also a particular form of clinical beriberi that occurs in patients who abuse alcohol, known as the Wer-nicke-Korsakoff syndrome. Subclinical deficiency may be revealed by reduced blood and urinary thiamin levels, elevated blood pyruvate/lactate concentrations and a-ketoglutarate activity, and decreased erythrocyte transketolase (ETKL) activity. Currently, the in vitro stimulation of ETKL activity by thiamin diphosphate (TDP) is the most useful functional test of thiamin status where an acute deficiency state may have occurred. The stimulation is measured as the TDP effect. 

Vitamin B1 (thiamine) has the active form, thiamine pyrophosphate. It is a cofactor of enzymes catalyzing the conversion of pyruvate to acetyl CoA, a-ketoglutarate to succinyl CoA, and the transketolase reactions in the pentose phosphate pathway. A deficiency of thiamine causes beriberi, with symptoms of tachycardia, vomiting, and convulsions. In Wernicke-Korsakoff syndrome (most common in alcoholics), individuals suffer from apa thy, loss of memory, and eye movements. There is no known toxicity for this vitamin. 

D. This patient has exhibited symptoms of beri beri heart disease, which is a result of a nutritional deficiency in vitamin Bj (thiamine). The active form of the vitamin, thiamine pyrophosphate, is a required cofactor for a-ketoglutarate dehydrogenase. 

Among secondary products, ketonic function compounds (pyruvic acid, a-ketoglutaric acid) and acetaldehyde predominantly combine with sulfur dioxide in wines made from healthy grapes. Their excretion is significant during the yeast proliferation phase and decreases towards the end of fermentation. Additional acetaldehyde is liberated in the presence of excessive quantities of sulfur dioxide in must. An elevated pH and fermentation temperature, anaerobic conditions, and a deficiency in thiamine and pantothenic acid increase production of ketonic acids. Thiamine supplementing of must limits the accumulation of ketonic compounds in wine (Figure 2.10). 

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