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Here, the non\u2010coenzyme action of thiamine on the major mammalian producers of pyridoxal\u20105\u2032\u2010phosphate (PLP), such as pyridoxal kinase (PdxK) and pyridoxine 5\u2032\u2010phosphate oxidase (PNPO), is characterized. Among the natural thiamine compounds, thiamine triphosphate (ThTP) is the best effector of recombinant human PdxK (hPdxK) <jats:italic>in vitro<\/jats:italic>, inhibiting hPdxK in the presence of Mg<jats:sup>2+<\/jats:sup> but activating the Zn<jats:sup>2+<\/jats:sup>\u2010dependent reaction. Inhibition of hPdxK by thiamine antagonists decreases from amprolium to pyrithiamine to oxythiamine, highlighting possible dysregulation of both the B<jats:sub>1<\/jats:sub>\u2010 and B<jats:sub>6<\/jats:sub>\u2010dependent metabolism in the chemical models of thiamine deficiency. Compared with the canonical hPdxK, the D87H and V128I variants show a twofold increase in <jats:italic>K<\/jats:italic><jats:sub>app<\/jats:sub> of thiamine inhibition, and the V128I and H246Q variants show a fourfold and a twofold decreased <jats:italic>K<\/jats:italic><jats:sub>app<\/jats:sub> of thiamine diphosphate (ThDP), respectively. Thiamine administration changes diurnal regulation of PdxK activity and phosphorylation at Ser213 and Ser285, expression of the PdxK\u2010related circadian kinases\/phosphatases in the rat brain, and electrocardiography (ECG). In contrast to PdxK, PNPO is not affected by thiamine or its derivatives, either in vitro or <jats:italic>in vivo<\/jats:italic>. Dephosphorylation of the PdxK Ser285, potentially affecting mobility of the ATP\u2010binding loop, inversely correlates with the enzyme activity. Dephosphorylation of the PdxK Ser213, which is far away from the active site, does not correlate with the activity. The correlations analysis suggests the PdxK Ser213 to be a target of kinase MAP2K1 and phosphatase Ppp1ca. Diurnal effects of thiamine administration on the metabolically linked ThDP\u2010 and PLP\u2010dependent enzymes may support the brain homeostatic mechanisms and physiological fitness.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15576-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15576","type":"journal-article","created":{"date-parts":[[2022,1,20]],"date-time":"2022-01-20T16:28:50Z","timestamp":1642696130000},"page":"20-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Thiamine\u2010dependent regulation of mammalian brain pyridoxal kinase <i>in vitro<\/i> and <i>in vivo<\/i>"],"prefix":"10.1111","volume":"161","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2552-8560","authenticated-orcid":false,"given":"Victoria","family":"Bunik","sequence":"first","affiliation":[{"name":"Belozersky Institute of Physico\u2010Chemical Biology Lomonosov Moscow State University  Moscow Russia"},{"name":"Faculty of Bioengineering and Bioinformatics Lomonosov Moscow State University  Moscow Russia"},{"name":"Department of Biochemistry Sechenov University  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasily","family":"Aleshin","sequence":"additional","affiliation":[{"name":"Belozersky Institute of Physico\u2010Chemical Biology Lomonosov Moscow State University  Moscow Russia"},{"name":"Department of Biochemistry Sechenov University  Moscow Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Nogues","sequence":"additional","affiliation":[{"name":"Research Institute of Terrestrial Ecosystems Italian National Research Council  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thilo","family":"K\u00e4hne","sequence":"additional","affiliation":[{"name":"Institute of Experimental Internal Medicine Otto\u2010von\u2010Guericke\u2010Universit\u00e4t Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Parroni","sequence":"additional","affiliation":[{"name":"Istituto Pasteur Italia\u2010 Fondazione Cenci Bolognetti and Department of Biochemical Sciences \u201cA. 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