Thiamine salvage

Thiamine pyrophosphate is the metabolically active form thiamine, also known as vitamin B1. Thiamine pyrophosphate is an important cofactor of enzymes of carbohydrate and amino acid metabolism such as pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, pyruvate decarboxylase and dihydrolipoamide dehydrogenase. Plants, bacteria and fungi can synthesise thiamine, whereas mammals salvage it from diet. Mammals possess the enzyme which catalyses pyro-phosphorylation of thiamine to thiamine pyrophosphate, thiamine diphosphokinase (TPK). Plasmodium falciparum can synthesise Thiamine phosphate (TMP) from 4-methyl-5-(2-phosphoethyl)-thiazole (THZ-P) and 4-amino-2-methyl-5-hydroxymethyl pyrimidine diphosphate (HMP-PP) by the action of the enzymes THZ kinase (ThiM), HMP/HMP-kinase (ThiD) and thiamine phosphate synthase (ThiE) in addition to salvaging thiamine from host (thiamine metabolism). ThiM and ThiD enzymes were biochemically characterised and the ability of ThiE in generating thiamine phosphate was studied in ThiE-negative Escherichia coli mutants. In addition, their expression in all blood stages of P. falciparum was observed [1, 2].The only enzyme missing in Plasmodium is thiamine phosphate kinase (ThiL) which is necessary for phosphorylation of de novo synthesised TMP. TPK, the enzyme involved in pyro-phosphorylation of salvaged thiamine to thiamine pyrophosphate is present in P. falciparum [2]. The analysis of kinetic parameters of P. falciparum TPK shows that it does not accept TMP as substrate [3] and this suggests that TMP needs to be dephosphorylated by a nonspecific phosphatase in order to be pyro-phosphorylated to TPP [4]. The analysis of Toxoplasma gondii gene models shows the absence of the enzymes catalysing de novo thiamine biosynthesis. As in mammals, it possesses the enzyme TPK and it can catalyse pyro-phosphorylation of thiamine salvaged from host to thiamine pyrophosphate, the active form of vitamin B1. The transporters involved in uptake of thiamine across parasite plasma membrane and translocation of active TPP across organellar membranes are not yet identified in both T. gondii and P. falciparum.

 

Enzyme EC Number Gene id Protein localisation Localisation data source
Thiamine diphosphokinase 2.7.6.2 TGME49_215250    

 

Open in a new window


 

Thiamine pyrophosphate dependent enzymes in T. gondii genome

 

Enzyme EC number Gene id Protein localisation Localisation data source
Pyruvate dehydrogenase E1 alpha subunit 1.2.4.1 TGME49_245670 Apicoplast Apiloc; Previous publication; Orthology transformation from P. falciparum
Pyruvate dehydrogenase E1 beta subunit 1.2.4.1 TGME49_272290 Apicoplast Apiloc; Previous publication
Oxoglutarate dehydrogenase E1 subunit 1.2.4.2 TGME49_244200 Mitochondrion Previous publication
Branched-chain alpha-keto-acid dehydrogenase E1 alpha chain 1.2.4.4 TGME49_239490 Mitochondrion Previous publication
Branched-chain alpha-keto-acid dehydrogenase E1 alpha chain 1.2.4.4 TGME49_292100    
Branched-chain alpha-keto-acid dehydrogenase E1 alpha chain 1.2.4.4 TGME49_314400 Mitochondrion Previous publication
Transketolase 2.2.1.1 TGME49_318310 Nucleus Previous publication