Thiamin and function of Thiamin
The intense research efforts that followed eventually :00 to the isolation of crystalline antiberiberi factor in :926 by jansen and Donath, who called it aneurine. Its hemical structure was identified 10 years later by "~illiams and Cline, who also accomplished the chemical synthesis of thiamin hydrochloride and showed it to be entical with the natural vitamin.The knovm biochemical functions of thiamin require its conversion to thiamin pyrophosphate (TPP), which serve as a coenzyme in a number of metabolic reactions. TPP is knovm also as cocarboxylase because one of its :najor functions involves an oxidative decarboxylation emoval of CO2) of alpha-ketoacids, of which pyruvate and alpha-ketoglutarate are most significant. Catabolism ;f the branched-chain amino acids involves a similar reaction.
Oxidative decarboxylation of pyruvate to acetyl coenzyme A (CoA) is a key reaction for further oxidation of carbohydrate and some amino acid substrates in the citric acid cycle (CAC) and for storage of excess carbohydrate as fat; this is discussed in Chapter 9 .Formation of succinyl CoA from alpha-ketoglutarate takes place in common pathway of energy metabolism in the CAC, thereby influencing the release of energy from proteins and also fats. Oxidative decarboxylation is a complex reaction with many steps, which in addition to TPP requires lipoic acid and the coenzymes of three other B-vitamins-pantothenic acid (CoA), riboflavin (FAD), and niacin (NAD)-thereby demonstrating the interde pendent roles of several of the B-vitamins in energy metabolism.
In thiamin deficiency pyruvic and alpha-ketoglutaric acids tend to accumulate in the body, and their levels in blood have been measured as a means of determining thiamin nutriture. However, more specific measures of thiamin status are now used more frequently.
TPP also participates in transketolations, which in volve the transfer of 2-carbon units (including a keto group) between several intermediates of the hexose mnonophosphate shunt (HMS), an alternate pathway of glucose metabolism. Active in red blood cells, and in liver, kidney, and other tissues, this pathway is important in providing 5-carbon sugars for the synthesis of various ribonucleotides, including those found in DNA and RNA. Normal functioning ofthe HMS also produces the reduced form of the niacin coenzyme, NADP, which is needed in several synthetic pathways, such as fatty acid, cholesterol,and steroid syntheses.
Measurement of the erythrocyte transketolase activity, which reflects the availability ofTPP in the tissues, has become a widely used method in the assessment of thiamin nu tri ture. Addi tion of exogenous TPP to a red cell hemolysate from a thiamin-deficient individual stimulates the activity of this enzyme by more than 25% under standardized conditions, whereas less than 150/0 stimulation is seen with a hemolysate from an individual with adequate endogenous TPP.
Thiamin deficiency generally affects the neural, cardiac, and gastrointestinal functions, and the symptoms in mild deficiency are nonspecific. Loss of appetite, constipation, irritability, and fatigue are all symptoms that have been associated with low thiamin intakes. Changes in the central nervous system affecting peripheral nerves, eye-hand coordination, and mental ability are found among chronic alcoholics who have inadequate intakes of thiamin. The various forms and symptoms of beriberi and the Wernicke-Korsakoffsyndrome are discussed in Chapter 21.
There is no well-defined relationship bet\-veen the biochemical abnormalities and the clinical manifestations that result from thiamin deficiency. Although failure to provide sufficient energy (A TP) to the cell, failure to produce a compound essential to the neuromuscular transmission (acetylcholine), and accumulation of "toxic metabolites" have been implicated in the nerve and muscle disease seen in thiamin deficiency, none of them adequately explains all the experimental observations and the specificity of thiamin in these conditions. 40,41
Research has demonstrated impaired synthesis of both fatty acids and cholesterol in certain types of brain cells cultured in a thiamin-deficient medium.42 It appears that the synthesis of the key enzymes that control fatty acid production is impaired in the absence of thiamin and can be restored by its addition to the culture medium. The mechanism by which thiamin regulates the production of these enzymes remains to be established as does the possible role ofthese biochemical defects in the manifestations of thiamin deficiency.
Rare genetic disorders causing various degrees of thiamin dependency have been reported. In children two cases of megaloblastic anemia have been identified which responded to large doses of thiamin but not to any of the other vitamins normally associated with this type of anemia.41 The metabolic defect has not been identified. Recently, a transketolase with lower than normal affinity to TPP has been discovered in cultured fibroblasts from four patients \vith the Wernicke-Korsakoff syndrome associated \vith a history of alcoholism. 43 These patients appear to require much more thiamin for normal functioning of this enzyme than is required by healthy people. The possible role of this enzyme in the development of the Wernicke-Korsakoff syndrome remains to be determined. Rare cases of branched-chain ketoaciduria (see maple syrup urine disease in Chap. 36) appear to involve an alpha-ketoacid decarboxylase with reduced affinity for TPP and respond to large doses of thiamin, whereas most cases of this disease do not.44
