Question

Which vital step(s) in metabolism is TPP important? Show key steps.

Answer 1

Thiamine Pyrophosphate - TPP is the active cofactor derived from thiamine(Vitamin B1).

TPP works as a coenzyme in many enzymatic reactions, such as:

1. Pyruvate dehydrogenase complex (AcetylCoA synthesis for acetylcholine)
   • pyruvate + CoA --> acetylCoA
2. Alpha-ketoglutarate dehydrogenase complex
   • Alpha-ketoglutarate + CoA --> succinylCoA
3. Branched-chain amino acid dehydrogenase complex
   • Leucine + CoA
   • Isoleucine + CoA
   • Valine + CoA
4. Transketolase
5. 2-hydroxyphytanoyl-CoA lyase
6. Pyruvate decarboxylase in ethanol fermentation.

TPP activates:

• the Krebs cycle (enzymes 1-3) and reduces glucose and pyruvate availability for synthetic pathways
• Transketolase (enzyme 4) that reduces the ribose-5P availability and the nucleotide synthesis.

TPP synthesis enzymes

1. thiamine pyrophosphokinase
   • Thiamine + ATP = TPP +AMP
   • TPP + ATP = TPPP + ADP
2. thiamine triphosphatase
   • TPPP--> TPP

TPP breakdown enzymes

1. nucleoside-triphosphatase, cancer-related substrates
   • TPP --> TP
   • ATP --> ADP
     • it is also expressed in many virus and parasites to increase their own DNA synthetic rate.

REGULATION

Calcium :Apparently Ca++ increase the activity of some of the enzymes using TPP

• A good correlation was obtained between the total calcium content and the activities of pyruvate dehydrogenase and oxoglutarate dehydrogenase.
• Ca and Tranketolase dimerization.

Transketolase proteins or transketolase enzyme activities have been related to neurodegenerative diseases, diabetes, and cancer.

Transketolase enzyme variants and reduced transketolase enzyme activities are present in patients with the neurodegenerative disease Wernicke-Korsakoff syndrome. In Alzheimer's disease patients transketolase protein variants with different isoelectric points or a proteolytic cleavage leading to small transketolase protein isoforms have been identified.

In diabetes mellitus patients reduced transketolase enzyme activities have been detected and the lipid-soluble thiamine derivative benfotiamine activates transketolase enzyme reactions, thereby blocking three major pathways of hyperglycemic damage and preventing diabetic retinopathy.

In cancer inhibition of transketolase enzyme reactions suppresses tumor growth and metastasis.