Thiamine Pyrophosphate (TPP)
Cofactors

Author: Gianpiero Pescarmona
Date: 01/01/2014

Description

Thiamine Pyrophosphate - TPP is the active cofactor derived from thiamine

In humans, TPP biosynthesis requires:

TPP in Human Metabolome Database

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 metabolism

Thiamine supply

Linus Pauling Foundation

Thiamine transport

DatabaseLinkLink
WikigenesSLC19A2SLC19A3

thiamine transporter expression

TPP synthesis

TPP synthesis enzymes
  1. thiamine pyrophosphokinase [EC:2.7.6.2: TPK1]
    • Thiamine + ATP = TPP +AMP
    • TPP + ATP = TPPP + ADP
  2. thiamine triphosphatase [EC:3.6.1.28: THTPA]
    • TPPP--> TPP
TPP breakdown enzymes
  1. nucleoside-triphosphatase, cancer-related (EC:3.6.1.15: NTPCR) substrates
    • TPP --> TP
    • ATP --> ADP
      • it is also expressed in many virus and parasites to increase their own DNA synthetic rate.

ENZYMES DEFINITION

A short protein description with the molecular wheight, isoforms, etc...
Use, when available, the link to Wikipedia (Es Trypsin)

THE GENES

DatabaseLinkLinkLink
WikigenesEC:2.7.6.2: TPK1EC:3.6.1.28: THTPAEC:3.6.1.15: NTPCR
GeneCards"EC:2.7.6.2: TPK1":"EC:3.6.1.28: THTPA":"EC:3.6.1.15: NTPCR":
Your Favorite Gene Sigma"EC:2.7.6.2: TPK1":"EC:3.6.1.28: THTPA":"EC:3.6.1.15: NTPCR":

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

Protein Aminoacids Percentage (Width 700 px)

SYNTHESIS AND TURNOVER

mRNA synthesis
protein synthesis

post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,
biological function

  • Enzymes
DatabaseLink
BRENDA - The Comprehensive Enzyme Information SystemEC:2.7.6.2: TPK1EC:3.6.1.28: THTPAEC:3.6.1.15: NTPCR
KEGG PathwaysEC:2.7.6.2: TPK1EC:3.6.1.28: THTPAEC:3.6.1.15: NTPCR
Human Metabolome DatabaseEC:2.7.6.2: TPK1EC:3.6.1.28: THTPA"EC:3.6.1.15: NTPCR":
  • Cell signaling and Ligand transport
  • Structural proteins

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

oxoglutarate dehydrogenase calcium

Virus

NTPases virus

Reducing TPP and TRK MORE R5P for viral nucleotides synthesis
h3. DIAGNOSTIC USE

Comments
2014-01-13T15:57:08 - Gianpiero Pescarmona

Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer., 2005

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. All the observed phenomena have been interpreted solely on the basis of a single transketolase gene (TKT) encoding a single transketolase enzyme. No mutations have been identified so far in TKT transketolase explaining the altered transketolase proteins or transketolase enzyme activities found in neurodegenerative diseases, diabetes and cancer. We demonstrate the presence of a second transketolase enzyme (TKTL1) in humans. During the evolution of the vertebrate genome, mutations in this transketolase gene (TKTL1) have led to tissue-specific transcripts different in size, which encode an enzymatically active transketolase protein as well as different smaller protein isoforms. The mutations within the TKTL1 gene caused a mutant transketolase enzyme with an altered substrate specificity and reaction modus. Here we characterize the TKTL1 gene and its encoded TKTL1 protein(s) and discuss the medical and clinical implications of this mutated transketolase. We furthermore postulate a novel metabolic concept for the understanding, prevention and therapy of neurodegenerative diseases, diabetes and cancer.

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