Interaction of pyridoxal 5-phosphate with apo-serine hydroxymethyltransferase

Jones, Clifton W.; Priest, David G.

doi:10.1016/0005-2744(78)90128-6

Cited by 16 publications

(7 citation statements)

References 17 publications

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“…Another effect of vitamin B 6 deficiency is the decreased activity of both cytosolic and mitochondrial SHMT, resulting in slower carbon transfer from serine to tetrahydrofolate. 42 Serine is the predominant, but not the only, source of one-carbon units for tetrahydrofolate. 43 This reduction in one-carbon substitution of tetrahydrofolate could slow down 5-MTHF formation and thereby impair homocysteine remethylation.…”

Section: Vitamin B 12 Deficiencymentioning

confidence: 99%

Folate Metabolism and Cardiovascular Disease

Smulders

Stehouwer

2005

Seminars in Vascular Medicine

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Folate is a water-soluble vitamin that occurs in different chemical forms distinguished by their oxidation state and the specific type of one-carbon substitution. Folates occur in natural food sources as reduced methylated or formylated tetrahydrofolate. Folic acid is a synthetic analogue with no metabolic activity of its own. Pharmacological doses of folic acid cause it to appear in plasma, where it has unknown, but potentially adverse, effects. This review discusses folate absorption, body distribution, and intracellular folate metabolism. The main physiological functions of folate can be classified as methylation and DNA synthesis. Several mechanisms act in concert to regulate the folate metabolic pathways to ensure that both functions of folate are fulfilled properly. B-vitamin deficiencies and genetic polymorphisms (particularly the C677T mutation in the methylenetetrahydrofolatereductase gene) have multiple effects on folate metabolism. Impairment of the methylation cycle, for example, leads to hyperhomocysteinemia, a proposed atherothrombotic factor. However, methylation disturbances also result in hypomethylation of DNA and other molecules, which may also contribute to the pathogenesis of cardiovascular disease. As cardiovascular researchers, we should try to develop a more integrative view on folate metabolism, rather than focusing merely on hyperhomocysteinemia.

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Section: Vitamin B 12 Deficiencymentioning

confidence: 99%

Folate Metabolism and Cardiovascular Disease

Smulders

Stehouwer

2005

Seminars in Vascular Medicine

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“…Studies of serine hydroxymethyl transferase (SHMT), a ubiquitous pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the transfer of the beta carbon (Cβ) of L-serine to tetra hydro pteroylglutamate (H 4 PteGlu) with formation of glycine and CH 2 -H 4 PteGlu, determined that the dissociation constant (K d ) values for binding of apo SHMT isoforms to cofactor are much greater than intracellular PLP concentration levels. SMHT from various sources was found to bind to cofactor with K d from 250 nM to as high as 27 µM 20 – 23 , while naturally occurring PLP levels in erythrocytes vary from 30 to 100 nmol/L of packed cells 24 , 25 , which indicates that SHMT activity should be sensitive to PLP concentration modifications. Studies reported changes of folate-mediated one-carbon metabolism through SHMT catalysis related to vitamin B6 availability in rat liver 26 , and in the MCF-7 human mammary carcinoma cell line 21 .…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

Machover

Almohamad

Castagné

et al. 2021

Sci Rep

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Supplementation of cancer cells exposed to 5-fluorouracil (FUra) and folinic acid (FA) with high concentration pyridoxal 5′-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of FUra in a synergistic interaction mode. We report a pilot study in 13 patients with previously untreated advanced carcinoma of the digestive tract to assess the impact of high-dose pyridoxine (PN) on the antitumor activity of regimens comprising FUra and FA. Five patients had colorectal adenocarcinoma (CRC); 5 had pancreas adenocarcinoma (PC); and 3 had squamous cell carcinoma of the esophagus (EC). Patients with CRC and with PC received oxaliplatin, irinotecan, FUra and FA, and patients with EC had paclitaxel, carboplatin, FUra and FA. PN iv from 1000 to 3000 mg/day preceded each administration of FA and FUra. Eleven patients responded. Two patients with CRC attained CRs and 3 had PRs with reduction rates ≥ 78%. Two patients with PC attained CRs, and 2 had PRs with reduction rates ≥ 79%. Responders experienced disappearance of most metastases. Of 3 patients with EC, 2 attained CRs. Median time to attain a response was 3 months. Unexpected toxicity did not occur. Results suggest that high-dose vitamin B6 enhances antitumor potency of regimens comprising FUra and FA.

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“…The rationale for the present hypothesis lies in the low affinity for binding of SHMT apoenzyme to cofactor. PLP was found to bind purified bovine liver SHMT1 with dissociation constant (K D ) as high as 27 mM (Jones and Priest, 1978), and it was reported to bind rabbit liver SHMT with a K D of 700 nM (Schirch et al, 1973). Human recombinant SHMT1 bound to cofactor with a K D of 850 nM in one study (Perry et al, 2007), and in another study human recombinant SHMT1 and SHMT2 bound to cofactor with K D of 250 and 440 nM, respectively (Giardina et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Enhancement of 5-Fluorouracil Cytotoxicity by Pyridoxal 5′-Phosphate and Folinic Acid in Tandem

Machover

Goldschmidt

Mollicone

et al. 2018

J Pharmacol Exp Ther

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The current study originates from the assumption that, in tumors, levels of naturally occurring pyridoxal 5'-phosphate (PLP) are too small to allow conversion of tetra hydro pteroylglutamate (HPteGlu) into methylene tetra hydro pteroylglutamate (CH-HPteGlu) in amounts required to improve inhibition of thymidylate synthase by 5-fluorouracil (FUra) through ternary complex stabilization. The hypothesis relates to the low affinity for cofactor of the PLP-dependent serine hydroxymethyl transferase (SHMT), the enzyme that catalyzes formation of CH-HPteGlu by transfer of the C of serine to HPteGlu. Intracellular concentrations of PLP are smaller than the dissociation constant of SHMT for cofactor, which suggests that enzyme activity should be sensitive to PLP level changes. Three cancer cell lines were supplemented with PLP to investigate the influence of this cofactor on FUra cytotoxicity. Cells were exposed to FUra, FUra and folinic acid (FA), FUra and PLP, and FUra combined with both FA and PLP. The median-effect principle for concentration-effect analysis and combination indices were used to determine interactions on cytotoxicity. FUra cytotoxicity in vitro was enhanced by FA and PLP in tandem. Synergistic cytotoxic interaction of FUra with FA and PLP was demonstrated in HT29 and L1210 cells. Summation was found in HCT116 cells. Parenteral pyridoxamine was administered in mice to explore erythrocyte production of PLP in vivo. Cofactor attained levels in the range of the K for binding to SHMT, and it was rapidly cleared from cells. Pharmacokinetics of pyridoxamine suggests that modulation of FUra by vitamin B6 could be achieved in vivo.

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Interaction of pyridoxal 5-phosphate with apo-serine hydroxymethyltransferase

Cited by 16 publications

References 17 publications

Folate Metabolism and Cardiovascular Disease

Folate Metabolism and Cardiovascular Disease

Pharmacologic modulation of 5-fluorouracil by folinic acid and high-dose pyridoxine for treatment of patients with digestive tract carcinomas

Enhancement of 5-Fluorouracil Cytotoxicity by Pyridoxal 5′-Phosphate and Folinic Acid in Tandem

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