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Metabolic Disorders

This presentation covers some of the diseases associated with intermediary metabolism & touches on vitamins as coenzymes

Jay Silveira

on 8 April 2016

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Transcript of Metabolic Disorders

What are some of the metabolic enzymes that utilize vitamin B2?
Metabolic Disorders - Objectives
List the B vitamins, indicate their common names and enzyme cofactor forms, and provide examples of metabolic enzymes that use them.
Explain the relationship between HIF-1 and glycolysis.
Describe the biochemical causes and effects of beriberi and mad hatter syndrome.
Discuss the origins and diagnostic challenges of mitochondrial disorders.

Citric Acid Cycle

Electron Transport Chain
In humans there are 13 vitamins: 4 fat-soluble (A, D, E and K) and 9 water-soluble (8 B vitamins and vitamin C).
The reason the set of vitamins seems to skip directly from E to K is that the vitamins corresponding to "letters" F-J were either reclassified over time, discarded as false leads, or renamed because of their relationship to "vitamin B", which became a "complex" of vitamins. The German-speaking scientists who isolated and described vitamin K (in addition to naming it as such) did so because the vitamin is intimately involved in the Koagulation of blood following wounding. At the time, most (but not all) of the letters from F through I were already designated, so the use of the letter K was considered quite reasonable. The following table lists chemicals that had previously been classified as vitamins, as well as the earlier names of vitamins that later became part of the B-complex:
Vitamin: B1 (Thiamine)
Coenzyme product: Thiamine Pyrophosphate
Deficiency: Beriberi
Vitamin: B2 (Riboflavin)
Coenzyme product: Flavin Coenzymes
Vitamin: B3 (Niacin)
Coenzyme product: Nicotinamide Coenzymes
Deficiency: Pellagra
Vitamin: B5 (Pantothenic Acid)
Coenzyme product: Coenzyme A
Vitamin: B6 (Pyridoxine)
Coenzyme product: Pyridoxal Phosphate
Vitamin: B7 (Biotin)
Coenzyme product: Biocytin
Glyceraldehyde 3-phosphate dehydrogenase
Alcohol dehydrogenase
Lactate dehydrogenase
Pyruvate dehydrogenase complex
Isocitrate dehydrogenase
Alpha-Ketoglutarate dehydrogenase complex
Malate dehydrogenase
NADH-Q oxidoreductase
Pyruvate dehydrogenase complex
Alpha ketoglutarate dehydrogenase complex
Succinate dehydrogenase
Succinate-Q reductase complex (Complex II)
NADH-Q oxidoreductase (Complex I)
Acyl Coa dehydrogenase
Pyruvate dehydrogenase complex
Citrate synthase
a-Ketoglutarate dehydrogenase complex
Succinyl CoA synthetase
Malate synthase
Pyruvate dehydrogenase complex
Alpha-Ketoglutarate dehydrogenase complex
Pyruvate carboxylase
Acetyl CoA carboxylase
Propionyl CoA carboxylase
Vital pathway - mutations in genes are rare

Tumors show enhanced glucose uptake and pathway activity (up to 200X).
Glycolytic enzymes
Low KM (high affinity) glucose transporters involved in basal glucose uptake.
HIF-1 also increases the expression of signal molecules like vascular endothelial growth factor (VEGF), which facilitates the growth of blood vessels.
Anaerobic exercise training evokes the same process.
In the absence of oxygen, HIF-1 increases the expression of most glycolytic enzymes as well as the highest affinity glucose transporters which transport glucose across the plasma membrane.
Beriberi is a neurological and cardiovascular disorder caused by a deficiency in thiamine (vitamin B1), initially described in Java in 1630.
In general, deficiencies in pathways of oxidative metabolism (PDH, CAC, ETC) are going to have the most noticeable affect those tissues that require relatively large amounts of energy.
Why are other tissues less affected?
In beriberi, the activities of the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes are low. Levels of pyruvate and alpha-ketoglutarate in the blood are higher than normal, and the increased pyruvate level is especially pronounced after the ingestion of glucose.
If pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activities were compromised, what might one expect to see in terms of levels of metabolic intermediates?
Three different enzymes are affected by thiamine deficiency:
Pyruvate dehydrogenase
Alpha-ketoglutarate dehydrogenase
Transketolase (pentose phosphate pathway)
Beriberi is characterized by:
Pain in the limbs
Weakness of the musculature
Distorted skin sensation
Possible enlarged heart and low cardiac output
Thiamine IS present in the husk of the rice, so if the whole grain is soaked prior to milling, some of the thiamine leaches into the kernel. Alternatively, the whole rice grain, or other whole grains, can be consumed.
Beriberi has been a health problem in the Far East because of the prevalence of rice (which has rather low thiamine content) in the diet.
What metabolic processes would be affected by a deficiency of thiamine (the precursor of thiamine pyrophosphate or TPP)?
U.S. long grain rice.
Photo by Keith Weller
Why does TPP deficiency lead to neurological disorders?
The nervous system relies on glucose as essentially its only source of energy, and the pyruvate produced in aerobic glycolysis can only enter the citric acid cycle through the pyruvate dehydrogenase complex.
Without the pyruvate dehydrogenase complex, the nervous system is without fuel.
Other tissues can use fats (triglycerides) as a source of fuel for the citric acid cycle.
The binding of mercury or arsenite to dihydrolipoyl groups inhibits PDH, but reducing agents such 2,3 mercaptopropanol can bind the metal ions and form a product that can be excreted in the urine.
Mad Hatter Syndrome

Mercury and arsenite are materials that have a high affinity for neighboring sulfhydryls, such as those in the reduced dihydrolipoyl groups of the pyruvate dehydrogenase complex.
Mad Hatter Syndrome

The term “Mad Hatter Syndrome” arose because felt hats (such as top hats) that were extremely popular in North America and Europe, were typically made through a process that required mercurous nitrate. The metal solution was used to roughen fur in the hats so it would mat down for further processing. Beaver fur, which was preferred, did not required this treatment, but since beaver fur was scarce and costly, other animals such as rabbits had to be used. Hatters were therefore exposed to high levels of mercury, which caused symptoms similar to those of beriberi.
The primary cause of mitochondrial disorders is a problem with the electron transport chain (ETC). These are the most common neurometabolic diseases in children. They affect ~ 1 in 5,000 to 1 in 10,000 kids, and are typically progressive and very difficult to diagnose and treat. Many mitochondrial diseases are still being discovered, understood, and characterized, but are estimated to be in the range of 10 to 15 per 1,000 people.

Mutations in Complex 1 are the most common, including impaired NADH utilization, or poor electron transfer to Q.

More recently, mitochondria have also been found to play a central role in programmed cell death, or apoptosis. One thought is that the accumulation of mutations in mitochondrial genes over the course of decades contributes to ageing, degenerative disorders, and cancer.
The severity of disease varies greatly since it is correlated with the percentage of mutated mitochondria, and mitochondria randomly segregate into daughter cells during mitosis.

The first mitochondrial disease to be characterized was Leber hereditary optic neuropathy (LHON), a form of blindness that strikes in midlife due to mutations in Complex 1.
Because of the way mitochondrial genes are inherited unequally from the two parents, the pathology of genetic mitochondrial diseases can be quite complex. All mitochondria are inherited solely from the mother, but only 13 of 80 peptides in the ETC are encoded by mitochondrial DNA, the rest are encoded by nuclear DNA, so most mitochondrial disorders do not follow maternal inheritance patterns.
Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule, and in most species codes for 13 or 14 proteins involved in the electron transport chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis). The number of proteins involved in the electron transport chain is much larger than 13 or 14, but the others are coded by the nuclear DNA. In total, the mitochondrion hosts about 3000 proteins, but only a subset (as described above) are coded on the mitochondrial DNA. Most of the 3000 proteins are involved in a variety of processes other than ATP production, such as porphyrin synthesis; only about 3% of the proteins are actually involved in ATP production.
Rocco Baldelli, AP, http://www.fannation.com
"When I say "fatigued" my body is literally spent after a very short amount of time out on the field which makes it extremely frustrating and difficult, but it's kind of a reality right now. I feel like I've done a serious workout after a very short period of time, and it's a very odd feeling. "I think the best way to describe it is literal muscle fatigue and cramping way before my body should be feeling these things. I would go out there and I was pretty much incapable of doing basic baseball activities, running and hitting and throwing. These were things I had done my whole life pretty easily and at some point within the last two years, we're not exactly sure why, these things started to change.''
Baldelli's mysterious illness
Posted: Thursday March 13, 2008 06:51AM ET (http://www.fannation.com)
Is Rocco Baldelli's baseball career finished? Baldelli and the Rays won't know how to respond to those questions or many others until they learn more about the "metabolic and/or mitochondrial abnormalities" that have sapped the 26-year-old's strength. Baldelli said the problem stems from his body's inability to produce energy in the form of adenosine triphosphate (ATP), which keeps his muscles from recovering like a normal person's during exercise.
Nutrients required in very small amounts for essential metabolic reactions in the body.
At least 13 vitamins required for humans.
Deficiencies of vitamins can result in diseases.
Why vitamins?
Where are all the vitamins designated by the other letters of the alphabet?
What are some of the metabolic enzymes that utilize vitamin B1?
What are some of the metabolic enzymes that utilize vitamin B3?
What are some of the metabolic enzymes that utilize vitamin B5?
What are some of the metabolic enzymes that utilize vitamin B6?
What are some of the metabolic enzymes that utilize vitamin B7?
Glycogen Phosphorylase
With an appropriate grasp of this material you should be able to...

Vitamin:B9 (Folic Acid)
Coenzyme product: Tetrahydrofolate
What are some of the metabolic enzymes that utilize vitamin B9?
Serine Hydroxymethyl Transferase
Methionine Synthase

What are some of the metabolic enzymes that utilize vitamin B12?
Vitamin:B12 (Cobalamin)
Coenzyme product: Methylcobalamin
Methylmalonly Coa Mutase
Methionine Synthase
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