Post by neurology admin on Oct 7, 2013 2:54:59 GMT -5
To understand the mechanisms through which thiamine deficiency, whether induced by alcoholism or other causes, leads to brain damage, one first must understand the normal role of thiamine in the cell. Investigations of this issue have focused on three enzymes that require thiamine as a cofactor. These enzymes are called transketolase, pyruvate dehydrogenase (PDH) and alpha–ketoglutarate dehydrogenase (á–KGDH); they all participate in the catabolism of sugar molecules (i.e., carbohydrates) in the body, as described in the following paragraphs. Each of these enzymes consists of several components that must be assembled to yield the functional enzyme, and the addition of thiamine is a critical step in this assembly process. As a result, thiamine deficiency causes suboptimal levels of functional enzymes in the cell, in addition to interfering with the activity of those enzymes.
Transketolase is an important enzyme in a biochemical pathway called the pentose phosphate pathway. In this set of biochemical reactions, a molecule called glucose–6–phosphate, which is derived from the sugar glucose, is modified by transketolase, yielding two products—a sugar called ribose–5–phosphate and a molecule called reduced nicotinamide adenine dinucleotide phosphate (NADPH) (see figure 2). Both of these molecules are essential for the production of numerous other important molecules in the cell. Ribose–5–phosphate is needed for the synthesis of nucleic acids, complex sugar molecules, and other compounds. NADPH provides hydrogen atoms for chemical reactions that result in the production of steroids, fatty acids, amino acids, certain neurotransmitters, and other molecules. In addition, NADPH plays an important role in the synthesis of glutathione, a compound that is essential in the body’s defense against oxidative stress. To function properly, all cells require certain levels of NADPH and ribose–5–phosphate, and the biochemical reaction mediated by transketolase is crucial for maintaining the appropriate levels of both molecules.
The other two enzymes requiring thiamine, PDH and á–KGDH, also participate in different steps of the breakdown and conversion of glucose–6–phosphate through two consecutive chains of biochemical reactions called glycolysis and the citric acid cycle (see figure 3). The main function of these pathways is the generation of a molecule called adenosine triphosphate (ATP), which provides energy for numerous cellular processes and reactions. Decreases in the activities of PDH and á–KGDH can result in reduced ATP synthesis, which in turn can contribute to cell damage and even cell death. In addition, proper functioning of PDH is essential for the production of the neurotransmitter acetylcholine as well as for the synthesis of a compound called myelin, which forms a sheath around the extensions (i.e., axons) of many neurons, thereby ensuring the ability of these neurons to conduct signals. The citric acid cycle and á–KGDH play a role in maintaining the levels of the neurotransmitters glutamate, gamma–aminobutyric acid (GABA), and aspartate, as well as in protein synthesis. Thus, the thiamine–using enzymes play numerous vital roles in the functioning of cells, and particularly of neurons.
pubs.niaaa.nih.gov/publications/arh27-2/134-142.htm
Transketolase is an important enzyme in a biochemical pathway called the pentose phosphate pathway. In this set of biochemical reactions, a molecule called glucose–6–phosphate, which is derived from the sugar glucose, is modified by transketolase, yielding two products—a sugar called ribose–5–phosphate and a molecule called reduced nicotinamide adenine dinucleotide phosphate (NADPH) (see figure 2). Both of these molecules are essential for the production of numerous other important molecules in the cell. Ribose–5–phosphate is needed for the synthesis of nucleic acids, complex sugar molecules, and other compounds. NADPH provides hydrogen atoms for chemical reactions that result in the production of steroids, fatty acids, amino acids, certain neurotransmitters, and other molecules. In addition, NADPH plays an important role in the synthesis of glutathione, a compound that is essential in the body’s defense against oxidative stress. To function properly, all cells require certain levels of NADPH and ribose–5–phosphate, and the biochemical reaction mediated by transketolase is crucial for maintaining the appropriate levels of both molecules.
The other two enzymes requiring thiamine, PDH and á–KGDH, also participate in different steps of the breakdown and conversion of glucose–6–phosphate through two consecutive chains of biochemical reactions called glycolysis and the citric acid cycle (see figure 3). The main function of these pathways is the generation of a molecule called adenosine triphosphate (ATP), which provides energy for numerous cellular processes and reactions. Decreases in the activities of PDH and á–KGDH can result in reduced ATP synthesis, which in turn can contribute to cell damage and even cell death. In addition, proper functioning of PDH is essential for the production of the neurotransmitter acetylcholine as well as for the synthesis of a compound called myelin, which forms a sheath around the extensions (i.e., axons) of many neurons, thereby ensuring the ability of these neurons to conduct signals. The citric acid cycle and á–KGDH play a role in maintaining the levels of the neurotransmitters glutamate, gamma–aminobutyric acid (GABA), and aspartate, as well as in protein synthesis. Thus, the thiamine–using enzymes play numerous vital roles in the functioning of cells, and particularly of neurons.
pubs.niaaa.nih.gov/publications/arh27-2/134-142.htm