MSCI530.thiamine
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ENZYMES IN CLINCAL MEDICINE
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Thiamine Metabolism
Name
Liberty University
MSCI 530: Introduction to Human Metabolism and Disease
26 January 2024
ENZYMES IN CLINCAL MEDICINE
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Thiamine Metabolism
Introduction
The water-soluble vitamin B1 or thiamine is an essential vitamin that is acquired through either dietary intake or supplementation (Lonsdale, 2006). Vitamins are often found in various forms, with thiamine being available in one free form and three phosphorylated forms, which include: thiamine monophosphate, thiamine diphosphate and thiamine triphosphate (Lonsdale, 2006). Thiamine diphosphate, also known as thiamine pyrophosphate (TPP) is the active form of thiamine (Pacei et al., 2020). Intaking a form of thiamine other than its free form requires the body to convert it into free thiamine through the body’s use of intestinal phosphatase (Lonsdale, 2006). Once the conversion process is complete, the jejunum becomes the site for absorption by the two thiamine transporters THTR-1 and THTR-2 before it is then transported into the bloodstream and moved into the cells where it is utilized for the metabolism of carbohydrates and energy (Lonsdale, 2006; Pacei et al., 2020). Any excess thiamine that is left over after the absorption is then excreted in urine through the renal system. Thiamine Significance
Several enzymes in the body are dependent on thiamine, including pyruvate dehydrogenase complex, transketolase, and α-ketolutarate dehydrogenase complex (Tylicki, 2018). An important enzyme in the pentose phosphate pathway (PPP), transketolase, of which thiamine is a cofactor, the PPP is responsible for the synthesis of both DNA and RNA in addition
to the regeneration of NADPH which is essential for the synthesis of glutathione and fatty acids (Lonsdale, 2006).
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Thiamine pyrophosphate is a significant cofactor in the pyruvate dehydrogenase complex, which is necessary for the oxidation of pyruvate into acetyl coenzyme A, a molecule that plays a crucial role in the metabolic reactions of protein, fats, and carbohydrates in the body (Patel et al., 2014). Lacking acetyl-CoA in the body can lead to a lack of energy and the ineffective production of glucose which lead to symptoms of fatigue and abnormal functioning of the brain (Patel et al., 2014; Glew & Rosenthal, 2009). Additionally, if the body is missing pyruvate dehydrogenase, the pyruvate becomes accumulated in the body, turning into lactic acid,
and ultimately leading to lactic acidosis (Patel et al., 2014; Glew & Rosenthal, 2009). Generated by pyruvate dehydrogenase, oxidized acetyl-CoA yields NADH and FADH2 which are necessary for the electron transport chain (Lonsdale, 2006). In a similar way to pyruvate dehydrogenase, there are three enzymes contained within the
α-ketolutarate dehydrogenase complex: thiamine pyrophosphate-dependent dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2), and dihydrolipoamide dehydrogenase (E3) (Treeter, 2005). Required for the production of ATP and the generation of energy, α-ketolutarate dehydrogenase complex is involved in the Krebs cycle, producing multiple chemical reactions. In addition to the aforementioned uses of α-ketolutarate dehydrogenase complex, it is also a cofactor for thiamine pyrophosphate which work together to convert α-ketolutarate into succinyl-
CoA, which without the a sufficient amount of thiamine pyrophosphate in the body, α-
ketolutarate builds up in excess, ultimately leading to the Krebs cycle breaking down (Lonsdale, 2006). Thiamine Deficiency - Disorders
A deficiency of thiamine can be the result of various different factors, including but not limited to poor dietary intake, alcoholism, and a renal system with a high clearance rate. Poor
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ENZYMES IN CLINCAL MEDICINE
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dietary intake of thiamine is typically seen more in undeveloped and developing countries where the diet consists mainly of polished grains (Wiley & Gupta, 2021). Alcoholism causes a thiamine
deficiency, as the GI tract is not able to absorb the vitamin properly or effectively. A deficiency of thiamine causes a low concentration of the enzymes which in turn leads to an impairment of important activities that take place and are required for multiple body processes. When thiamine stores are depleted in the body, it takes as little as four weeks before complications such as beriberi (both wet and dry) and Wernicke-Korsakoff syndrome can be noted in an individual. One of the first symptoms indicating an issue is a temporarily altered mental status caused by Wernicke encephalopathy (Wiley & Gupta, 2021). If this condition is left untreated and the thiamine is not replaced, permanent mental decline will be noted as a result
of atrophy to the brain (Wiley & Gupta, 2021). Symptoms of poor reflexes and motor deficits are
seen in the complication of dry beriberi, while edema and heart failure are symptoms noted in wet beriberi (Sriram, 2012). Conclusion
It is easy to see that thiamine is an extremely important vitamin needed in the body for it to perform at an optimal level. If allowed to become deficient in the body, many of the processes that are required will not take place and will quickly result in symptoms that are indicative of crucial issues. If left untreated, these temporary symptoms can easily become permanent and lead to long-term concerns for an individual.
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References
Glew R, Rosenthal M. (2009). Medical Biochemistry: Human Metabolism in Health and Disease
(1
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ed). New Jersey, Wiley Publishers, ISBN: 978-0-470-12237-2.
Lonsdale D. (2006). A review of the biochemistry, metabolism and clinical benefits of thiamin(e)
and its derivatives. Evid Based Complement Alternat Med, 3(1),
49-59. https://doi.org/10.1093/ecam/nek009
Pacei F, Tesone A, Laudi N, et al. (2020). The Relevance of Thiamine Evaluation in a Practical Setting. Nutrients, 12(9), 2810
. https://www.doi.org/10.3390/nu12092810
Patel MS, Nemeria NS, Furey W, Jordan F. (2014). The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem, 289(24), 16615-16623. https://www.doi.org/10.1074/jbc.R114.563148
Sriram K, Manzanares W, Joseph K. (2012). Thiamine in nutrition therapy. Nutr Clin Pract
, 27(1),
41-50. https://www.doi.org/10.1177/0884533611426149
Tretter L, Adam-Vizi V. Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2335-2345. doi:10.1098/rstb.2005.1764
Tylicki A, Łotowski Z, Siemieniuk M, Ratkiewicz A. (2018). Thiamine and selected thiamine antivitamins - biological activity and methods of synthesis. Biosci Rep, 38(1).
https://www.doi.org/10.1042/BSR20171148
Wiley KD, Gupta M. Vitamin B1 Thiamine Deficiency. (2021). StatPearls. Treasure Island (FL):
StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK537204/