Abstract
Thiamine (Vitamin B1) is an essential vitamin that must be obtained from the diet for proper neurological function. At higher doses, thiamine and benfotiamine (S-benzoylthiamine O-monophosphate, BT)–a phosphorylated derivative of thiamine–have antinociceptive effects in animals and humans, although how these compounds inhibit pain is unknown. Here, we found that Prostatic acid phosphatase (PAP, ACPP) can dephosphorylate BT in vitro, in dorsal root ganglia (DRG) neurons and in primary-afferent axon terminals in the dorsal spinal cord. The dephosphorylated product S-benzoylthiamine (S-BT) then decomposes to O-benzoylthiamine (O-BT) and to thiamine in a pH-dependent manner, independent of additional enzymes. This unique reaction mechanism reveals that BT only requires a phosphatase for conversion to thiamine. However, we found that the antinociceptive effects of BT, thiamine monophosphate (TMP) and thiamine–a compound that is not phosphorylated–were entirely dependent on PAP at the spinal level. Moreover, pharmacokinetic studies with wild-type and Pap−/− mice revealed that PAP is not required for the conversion of BT to thiamine in vivo. Taken together, our study highlights an obligatory role for PAP in the antinociceptive effects of thiamine and phosphorylated thiamine analogs, and suggests a novel phosphatase-independent function for PAP.
Highlights
In mammals, thiamine is an essential dietary supplement and is important for neurotransmission and neurological function [1,2,3,4,5]
Peaks for O-BT and thiamine appeared at all pH values, with O-BT production favored at pH 7.0, and thiamine production favored at pH 8.5
To determine if thiamine could be generated in a non-enzymatic fashion from S-BT and O-BT, we purified the S-BT and O-BT reaction intermediates by high-performance liquid chromatography (HPLC; Fig. 2A and 3A, respectively), monitored the stability of these compounds in the absence of enzymes
Summary
Thiamine is an essential dietary supplement and is important for neurotransmission and neurological function [1,2,3,4,5]. Thiamine is absorbed in the intestine and transported from the extracellular space by thiamine transport receptors (THTR1 and THTR2, called SLC19A2 and SLC19A3, respectively) [6,7,8]. Thiamine exists as the free molecule as well as in the form of several phosphate esters: thiamine monophosphate (TMP), thiamine diphosphate (TDP, called thiamine pyrophosphate), and thiamine triphosphate (TTP) [9]. TDP is an important coenzyme in several biochemical processes, including carbohydrate and amino acid metabolism [10,11,12]. Prokaryotes and eukaryotes contain a diverse repertoire of thiamine analogs
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