Thiamine pyrophosphate: An essential cofactor for the α-oxidation in mammals – implications for thiamine deficiencies?

Abstract

The identification of 2-hydroxyphytanoyl-CoA lyase (2-HPCL), a thiamine pyrophosphate (TPP)-dependent peroxisomal enzyme involved in the alpha-oxidation of phytanic acid and of 2-hydroxy straight chain fatty acids, pointed towards a role of TPP in these processes. Until then, TPP had not been implicated in mammalian peroxisomal metabolism. The effect of thiamine deficiency on 2-HPCL and alpha-oxidation has not been studied, nor have possible adverse effects of deficient alpha-oxidation been considered in the pathogenesis of diseases associated with thiamine shortage, such as thiamine-responsive megaloblastic anemia (TRMA). Experiments with cultured cells and animal models showed that alpha-oxidation is controlled by the thiamine status of the cell/tissue/organism, and suggested that some pathological consequences of thiamine starvation could be related to impaired alpha-oxidation. Whereas accumulation of phytanic acid and/or 2-hydroxyfatty acids or their alpha-oxidation intermediates in TRMA patients given a normal supply of thiamine is unlikely, this may not be true when malnourished.

RP-HPLC-fluorescence analysis of aliphatic aldehydes: application to aldehyde-generating enzymes HACL1 and SGPL1

“…A gender dependency, so far not reported, was found (106 ± 12 mU/g liver in females, n = 4, and 71 ± 19 mU/g liver in males, n = 6). The values obtained were comparable to those previously measured in rodent liver homogenates using long-chain 2-hydroxyacylCoA as substrate ( 5,6,23 ). Linearity of HACL1 activity in mouse liver homogenates is limited to 5 min (at 1 mg (40 M).…”

“…To simulate HACL1 defi ciency, so far not yet reported, HACL1 activity was measured in human fi broblasts exposed to oxythiamine (OT), which blocks the coenzyme functions of thiamine. In fact, OT-diphosphate competes with TPP for binding to apo-enzymes ( 23 ). As reported before, OT exposure resulted in inhibition of ␣ -oxidation ( 23 ) and reduced HACL1 activity ( Fig.…”

“…At the time of the experiment, mice were anesthetized with an overdose of Nembutal (approximately 150 g/g body weight), and tissues were dissected. Human fi broblasts ( 23 ) and murine fi broblasts, derived from C57BL6 or Sgpl1 Ϫ / Ϫ mice ( 24,25 ), were cultured as described in the cited references .…”

Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism

“…Given extracellularly, the majority of 2OH-FA appear to be degraded, with few molecules being incorporated into structural lipids ( 19,59,60 ). The steps involved in the degradation of 2OH-FA are an activation, uptake of the…”

Wild birds of declining European species are dying from a thiamine deficiency syndrome

“…Thiamine (T), vitamin B 1 , is a water-soluble vitamin essential for vertebrates. Inside the cell, T is phosphorylated (10) to thiamine diphosphate (TDP), which functions as a cofactor for at least 5 vital enzymes in the cellular metabolism: transketolase (TK) in the hexose monophosphate shunt, pyruvate dehydrogenase in the glycolysis, ␣-ketoglutarate dehydrogenase (KGDH) in the citric acid cycle, branched-chain ␣-keto acid dehydrogenase for the metabolism of amino acids, and, as recently shown, 2-hydroxyacylCoA lyase 1 for the ␣-oxidation of 3-methyl-branched and 2-hydroxy straight chain fatty acids (11,12). Further phosphorylation produces thiamine triphosphate, which is necessary for the proper functioning of neuronal membranes (13,14).…”