Thiamin Flashcards
1
Q
What is the history of the discovery of Thiamin?
A
- First described water-soluble vitamin
- 1884: Dr. Takaki hypothesized that beriberi was caused by dietary insufficiency
- 1897: Christiaan Eijkman - paralysis in birds fed cooked, polished rice. Reversed when rice polishing stopped. (Nobel prize)
- 1901: essential nutrient in the outer layer of the grain
- ’20s and ’30s: isolation, structure and synthesis of thiamin: “sulfur-containing vitamin”
2
Q
What is B1 called?
A
Thiamin
3
Q
What are the properties of thiamin?
A
- Colorless, water soluble
- Not stable in UV light, moisture, alkaline/neutral solutions
- Pyrimidine + thiazole
- Active site on C2 of thiazole. Can accept and donate molecule
- Active site important for what reactions it goes through and how it impacts metabolism
4
Q
What is the active form of B1?
A
- ThDP or TPP (thiamin pyro/diphosphate) is the active (coenzyme) form of thiamin (80%)
- Can also exist as mono-and tri-phosphate forms
- Thiaminylated adenines
- Pyrophosphate coenzyme = active form. Enzyme activates the vitamin
- Thiamin + 2 phosphates added
5
Q
Explain how thiamin is activated
A
- ThMP is the active form. Phosphatase can remove a phosphate to get a thiamin
- ATP and magnesium can be added to thiamin to form free ThDP through thiamin pyrophosphokinase
- thDP can be bound, converted to ThTP or AtHTP
- ThDP converted to ThMP if phosphate is removed through thiamin diphosphatase
- Adenylate kinsase and ATP and magnesium converts free ThDP to ThTP
- ThTP converted to ThDP via thiamin triphosphatase (removal of P)
- ThDP adenylyl transferase converts ThDP to AthTP with ADP
6
Q
What does a phosphatase do? What does a kinase do?
A
Phosphatase: Removes phosphate
Kinase: Uses ATP to add a phosphate
7
Q
What is the metabolic role of thiamin?
A
- Coenzyme in >24 enzymes
- Plays a role in:
→ Nervous system function: role in nerve conduction and in neural meembranes
→ Energy production
→ Biosynthesis of lipids
8
Q
What are the coenzyme vitamins?
A
- B vitamins, vitamin C, and vitamin K
9
Q
What do coenzymes do?
A
- Some vitamins form part of the coenzymes that enable enzymes either to synthesize compounds
- Bind to proteins to help it do its activity
- Without coenzymes protein does not work
10
Q
Thiamin is involved in the oxidative decarboxylation of alpha-keto acids. What three examples are given in class of this?
A
- Pyruvate dehydrogenase complex
- Alpha-ketoglutarate dehydrogenase
- Branched-chain alpha-keto acid dehydrogenase
All involve breaking down metabolites for energy
11
Q
What three major impacts does thiamin have on the metabolism?
A
- Oxidative decarboxylation of alpha-keto acids (energy metabolism)
- Transketolation (Converting sugars)
- Alpha-oxidation of phytanic acid (found in meat, dairy, fish) (breaking down phytanic acid)
12
Q
Thiamin is involved in transketolation. What is the example of this given in class?
A
Interconversions of sugar phosphates in pentose phosphate shunt
13
Q
Thiamin is involved in alpha-oxidation of phytanic acid. Give examples of these given in class.
A
- 3-methyl-substituted fatty acid = cannot undergo Beta oxidation
- Genetix enzyme disorders can cause buildup of phytanic acid and lead to Refsum’s disease.
14
Q
Where are B vitamins involved in glycolysis?
A
- Involved in the conversion of pyruvate to acetyl-CoA (PDC) and the TCA cycle
- B vitamins involved throughout the cycle
- CoASH
- FADH2
15
Q
How is thiamin involved in the pyruvate dehydrogenase complex?
A
- Green = B vitamins. CoA-SH, TPP, FAD, NAD
- TPP: thiamin pyrophosphate binds to pyruvate and get CO2 produced
- CHOH = acetyl compound that makes acetyl CoA later
- Thiamin accepts and donates acetyl groups
- Without thiamin would not be able to break down pyruvate
16
Q
Explain how thiamin is involved in alpha-ketoglutarate dehydrogenase
A
- Alpha ketoglutarate + NAD and CoA converted to succinyl CoA by alphaketoglutarate dehydrogenase
- Involves the removal of carbon dioxide from alpha ketoglutarate
17
Q
How is thiamin involved with branch chain amino acids?
A
- Need thiamin for BCAA catabolism
- If you do not have thiamin have a build up of BCAA and Keto acids and would not be able to break them down to get acetyl coA or succinyl CoA
- BCAA deaminated to form ketoacids
- Ketoacids then go through TPP dependent decarboxylation by alpha keto acid decarboxylase to form succinyl CoA and acetyl CoA
- **TPP needed to decarboxylate deaminated BCAA to get energy from amino acids
18
Q
Explain how thiamin is involved in branched-chain alpha-keto acid dehydrogenase
A
- BCAA convertd to keto acids
- Keto acids enter into mitochondrial BCKD complex form CoA complexes using CoA-SH and NAD
- Need thiamin for CoA-SH and NAD
- This enzyme complex catalyzes the oxidative decarboxylation of branched, short-chain alpha-ketoacids
19
Q
Explain how thiamin is involved in the pentose phosphate pathway
A
- one type of sugar is converted to a different type of sugar
- Glucose converted to G6P
- G6P enters PPP to form Ribose-5-Phosphate and NADPH
- Ribose-5-Phosphate can be used for nucleic acids, complex sugars, and coenzymes
- NADPH for coenzymes, steroids, fatty acids, amino acids, neurotransmitters, and glutathione
20
Q
What is the function of transketolase?
A
- TPP involved with Transketolase
- Causes conversion of xylose-5-phosphate to G3P and another byproduct
- This by product can be converted into ribose-5-P and erythrose-4-P which can be furthur converted
- A way of getting the sugars we need in our cells
- TPP is the way in which the enzyme moves the carbons around!
- Has a role in metabolism and a clinical function which should be monitored
21
Q
Summarize the metabolic role of thiamin
A
- TPP Transketolase in the PPP to convert Ribose 5 phosphate to G3P
- Conversion to pyruvate
- Pyruvate converted to acetyl-CoA by TPP PDC
- TPP alphaketoglutarate dehydrogenase in the CAC
- BCAA broken down by TPP BCKDH to Branched cain acetyl CoA to be used in CAC
22
Q
What will occur to phytanic acid levels when there is a B1 deficiency?
A
- No thiamin can have a build up of phytanic acid which can cause neurological disorders
- Alpha oxidation of phytanic acid does not occur and leads to Refsum’s disease (nerves don’t work properly, neurodegenerative disease)
- Genetic enzyme (phytanoyl-CoA hydrolase) disorder leads to build up of phytanic acid
23
Q
How is thiamin absorbed?
A
- TPP and TMP in diet broken down to thiamin by pyrophosphatases
- Thiamin in low levels will be transported into enterocyte by SLC19A2/3 (mainly through this way)
- Thiamin in high levels >5mg/day diffuse directly into enterocyte
- Once in cell converted to active TPP/TMP by phosphorylation via TPK (thiamin pyrophosphokinase)
- Thiamin goes into portal circulation to liver where conversion can also occur. What it doesn’t need will go to muscle where most of it is stored
24
Q
What is metabolic trapping?
A
- To keep nutrient within the cell will add phosphate charges and make thiamin bigger and more charged so it isn’t easily transported out
- In plasma: free thiamin and TMP
- In cellular compartments: TPP
25
Where is most of the thiamin stored in our body?
- Only small amount (~30mg) stored in body
→ 80% as TPP (metabolically trapped form), 10% TTP, rest as thiamin and TMP
- Mostly in skeletal muscle (50% body thiamin), as well as liver, kidney, and nervous tissues
- High metabolic rate + low storage amounts = daily intake necessary. See deficiency in weeks
26
What form is thiamin in in our food?
- Main form are coenzyme/cofactor form of TPP/TMP
- Converted to thiamin in the body for transport
27
How is thiamin excreted?
- Reabsorbed in renal brush border membrane via saturable carrier-mediated transport system
- Thiamin consumed in excess of tissue needs is rapidy excreted (water soluble)
- Several metabolites arise from the action of gut microflora (not an important producer of thiamin for our bodies
- Good at maintaining levels when we need it. Reabsorb thiamin by kidneys back into circulation
28
What are the food sources of thiamin?
- Thiamin synthesized by plants and some micro-organisms (not animals)
- Humans require dietary thiamin - we do not make it ourselves
- Plant sources:
→ Unrefined/whole grains, nuts, legumes
→ Enriched flour, grains, bread, cornmeal
- Animal sources:
→Mainly phosphorylated forms (because it is in our muscle)
→ Organ meat and (lean) pork
→ Milk and eggs
29
How is thiamin reduced/destroyed in food?
- Boiling/blanching reduces them
- Thiamin can be destroyed by:
→ Baking soda
→ UV
→ Thiaminases (enzymes that breakdown thiamin) in raw freshwater fish, shellfish, and ferns
→ Heat-stable antagonist (caffeic acid and tannic acid; found in coffee, tea, Brussels sprouts, rice bran)
→ Sulfite (high in processed food - preservative)
30
What are thiamin requirements altered by?
- Related to total energy intake → involved in metabolism of CHO, lipids, and proteins
- May be elevated in those with high caloric requirements. E.g. patients on dialysis, long-term IV-feeding and chronic infection
- Requirements can be altered by:
→ Thiaminases
→ Thiamin antagonists
→ Vitamin C: may counteract anti-thiamin activity of tannic acid
31
What is the thiamin recommendation?
- 0.4mg/1000kcal a day (for 2000+ kcal diets) but no less than 1.0mg
- No UL set due to lack of reported adverse effects
32
How can you determine thiamin status?
- Urinary excretion
- Blood pyruvic acid or alpha-ketoglutarate
→ Increase in thiamin deficiency
→ Problem = not sensitive enough to ID early deficiency and is non-specific
→ %TPP effect (AC)
33
What is the TPP effect?
- Transketolase activity (blood or erythrocytes)
- TPP effect: if activity increases with added TPP, blood is not saturated with TTP
- Values: %TPP effect (AC):
→ Adequate: <15% (1-1.15)
→ Marginal: 16-20% (1.16-1.20)
→ Deficient: >20% (>1.20)
Activity coefficient (AC): +TPP/-TPP
% Stimulation = (AC*100)-100
34
What are the populations at risk of thiamin deficiency?
- Low intake
→ Developing world where polished rice is main staple (getting a lot of calories but not the main staple)
→ Elderly living at home (tea and toast)
→ Children who eat mostly snack food and have unbalanced diets
- GI disorders
- Periods where there is increased CHO metabolism (pregnancy, lactation, growth)
- Genetic disorders (i.e. enzyme systems)
35
What are the clinical signs of thiamin deficiency?
- Decreased urinary excretion of thiamin (transporter in kidneys will try to retain as much as they can during starvation)
- Decreased erythrocyte transketolase activity
- Usually occurs along with deficiencies of other B vitamins
36
In marginal and severe thiamin deficiency what will you see?
- Marginal: see symptoms after 21-28 days of dietary inadequacy
→ tired, irritable, depression, weight loss
→ Loss of appetite, sometimes nausea and vomiting
- Severe = Beriberi
37
What are the symptoms of wet beriberi?
- Cardiovascular effects
- Lactic acidosis
- Accumulation of lactic acid → edema → cardiac output increased → myocardial exhaustion
- Results from severe physical exertion + high CHO intake and chronic thiamin deficiency
- Have enough calories coming in and doing a lot of physical work but not getting enough micronutrients so do not have cofactor to break down pyruvate and build up lactate
38
What are the symptoms of dry beriberi?
- Neuritic (neurological disease)
- Peripheral neuropathy; tingling, numbness, weakness
- Myelin degeneration
- Due to inactivity + caloric restriction and chronic thiamin deficiency
- No calories coming in; starvation situation so no thiamin and main symptoms are neurological - mental issues
39
Alcoholism can ead to what two things?
- Wernicke and korsakoff
40
What is wernicke?
- similar symptoms to dry beri beri
- Neurological disorder
- Diplopia (double vision), nystagmus (rapid eye movement), ataxia (uncoordinated gait)
41
What is Korsakoff?
- Deficiency of thiamin has similar symptoms to dry beri beri
- Psychosis/abnormal mental state
- Memory loss, inability to learn new information, confusion
42
What has research found about thiamin?
- Diabetes might be a state of "relative" thiamin deficiency
→ current trials to see if thiamin or benfotiamine (lipophilic derivative) may counteract the damaging effects of hyperglycemia on vascular cells
- Reports of severe thiamin deficiency after surgery for obesity = "bariatric beriberi"
→ frequent complication is Wernicke encephalopathy
→ Thiamin deficiency induced by → food intake and repeated vomiting
