Thiamin Flashcards
Thiamin History
- First described as 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”
Properties of thiamin
- colorless
- water soluble
- not stable in UV light, moisture, alkaline/neutral solutions
Structure and active site of thiamin
the double bond of the thiazole
What is the active form of thiamin act as?
A co-enzyme
What is the active form of thiamin?
Thiamin pyrophosphate (or diphosphate) so it has 2 phosphates attached to the alcohol
TPP/TDP
thiamine pyrophosphate/diphosphate
Properties of the active form of Thiamin
- TPP
- can also exist as mono- and tri-phosphate forms (but these are not active)
- thiaminylated adenines (nucleotides)
Metabolic role of thiamin
Coenzyme in >24 enzyme that plays a role in:
* Nervous system function (role in nerve conduction & in neural membranes)
* Energy production
* Biosynthesis of lipids
What vitamins act as coenzymes?
- B vitamins
- vitamin C
- vitamin K
How does coenzyme action work?
Bind to enzymes which enable them to perform activity to either synthesize compounds or dismantle them. Without coenzymes the substrate do not respond, so the vitamin creates an attractive force so that the enzyme recognizes the substrates
Metabolic reactions TPP is involved in
- oxidative decarboxylations of α-keto acids
- transketolation
- α-oxidation of phytanic acid
Enzymes for oxidative decarboxylations of α-keto acids of which TPP is a co enzyme
Involved in breaking down metabolites for energy
* pyruvate dehydrogenase complex
* α-ketoglutarate dehydrogenase
* branched-chain α-keto acid dehydrogenase
What does PDH do?
Makes Acetyl CoA from pyruvate which then enters into the CAC; NAD+ →NADH, releases CO2
* E1: pyruvate dehydrogenase
* E2: Dihydrolipoyl transacetylase
* E3: Dihydrolipoyl dehydrogenase
Role of TPP in PDH
Involved in the first E1 with pyruvate dehydrogenase where TPP accepts and donates acetyl groups from pyruvate and CO2 is released.
* The acteyl binds to the active site of TPP
What does α-ketoglutarate dehydrogenase do?
Part of the CAC, converting α-ketoglutarate → Succinyl CoA; NAD→NADH, releases CO2
Role of TPP in α-ketoglutarate dehydrogenase
Present on the enzyme and the active site is what accepts the carbon structure so that it can be transferred to CoA-S
What does Branched-chain α-keto acid dehydrogenase do?
Enzymes that breaks down AAs so we can get energy from them
* Deamination
* TPP dependant decarboxylation
Role of TPP in Branched-chain α-keto acid dehydrogenase.
Required in the α-keto acid decarboxylation and without it there would be a build up of branched chain AAs and could not produce energy
What is transketolation?
Interconversion of sugar phosphates in in the pentose phosphate pathway
* The enzyme transketolase is a way we get the sugars we need in our cells
Role of TPP in transketolation
TPP moves the carbons around to make new sugars
* TPP is attached to transketolase and a 2 carbon structure from the sugar attaches to the TPP and depending on enzyme present the 2-C structure will transfer to a sugar and make a new one by adding on two Carbons
From the PPP what is ribose-5-phosphate and the NADPH go towards?
- ribose-5-phosphate: nucleic acids, complex sugars, coenzymes
- NADPH: coenzymes, steroids, fatty acids, amino aicds, neurotransmitters and glutathione
Role of thiamin in 𝝰-oxidation of phytanic acid?
Thiamin is attached to the enzyme phytanoyl-CoA hydrolase which gets rid of the methyl group of phytanic acid to prevent build up since it cannot undergo β-oxidation
Location of PDH, KDH, BCKDH, and transketolase
- PDH, KHD, BCKDH: mitochondria
- Transketolase: cytosol
What is phytanic acid?
3-methyl-substituted fatty acid which we don’t usually make but it is found in meat, dairy and fish which cannot undergo β-oxidation
What happens with a disorder of the phytanoyl-CoA hydrolase enzyme?
Can cause buildup of phytanic acid and lead to Refsum’s disease
* A rare genetic disease that causes weakness or numbness of the hands and feet (peripheral neuropathy)
How is thiamin absorbed?
In our diet it is often in the active form because that is how it is present in the foods. We dont absorb large molecules or those will lots of charge very well, however. It is first broken down to its vitamin form, so the phosphates of TPP are removed via pyrophosphatases. Thiamin has a transporter into the enterocyte which is the main route and then some diffusion. Once in the enterocyte can be activated to TPP (via TPK) and used within the enterocyte, but most will be absorbed into circulation and hit liver first to be used. What the liver does not need leaves and goes to other tissues especially muscle which uses the most thiamin since it uses a lot of energy.
How is thiamin present in circulation vs. cells?
- plasma: free thiamin and TMP
- cellular compartment: TPP
How does the thiamin remain in a cell?
metabolic trapping
* Adding the phosphate groups gives the charge so they cant leave
Thiamin storage
only small amount (~30 mg) stored in the body which is mostly in skeletal muscle (50% body thiamin), as well as liver, kidney, & nervous tissues
* 80% as TPP, 10% TTP, rest as thiamin & TMP
* high metabolic rate + low storage amounts = daily intake necessary
Why of the thiamin found in the muscle?
Most of our energy is burned here
Thiamin excretion
- Thiamin consumed in excess of tissue needs is rapidly excreted; water soluble so easy to excrete
- Reabsorbed in renal brush border membrane via saturable carrier-mediated transport system; transporters are good at maintaining levels where we need it.
Where else might thiamin come from besides diet?
Several metabolites arise from the action of gut microflora
* Not a significant producer
Need to confirm what this is rtalking about
What are the sources of thiamin?
- plants: synthesizedbyplantsandsomemicro- organisms (not animals)
- animals: Not synthesized but stored in the muscle so the phosphorylated form
plant sources of thiamin
- unrefined/whole grains, nuts, legumes
- Enriched flour, grains, bread, cornmeal
animal sources of thiamin
Will need to be dephosphorylated
* organ meat and (lean) pork
* milk and eggs
What cooking process reduces thiamin?
Boiling/blanchingreducesthiamin
What processes can destroy thiamin?
- baking soda
- UV
- Thiaminases (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)
What determines thiamin requirements?
Related to total energy intake
* Involved in metabolism of CHO, lipids and proteins
When might elevated thiamin be seen?
those with high caloric requirements:
* e.g. patients on dialysis, long-term IV-feeding and chronic infection
How can thiamin requirements be altered?
- Thiaminases - lower
- Thiamin antagonists - lower
- Vitamin C: may counteract anti-thiamin activity of tannic acid
- Higher metabolic rate may require more
RDAs for thiamin
0.4 mg/1000 kcal/day (for 2000+ kcal diets) but no less than 1.0 mg
* no UL set due to lack of reported adverse effects
How to determine thiamin status
- urinary excretion
- blood pyruvic acid or α-ketoglutarate
- transketolase activity
What is urinary excretion to determine thiamin status typically used for?
Mostly used for rough estimations of a population but not usually the individual
How does blood pyruvic acid or α-ketoglutarate determine thiamin status?
↑ in thiamin deficiency
* problem = not sensitive enough to ID early deficiency & is non-specific
