Effect of tryptophan metabolites on the activities of rat liver pyridoxal kinase and pyridoxamine 5-phosphate oxidase <i>in vitro</i>

Takeuchi, Fumio; Tsubouchi, Ryoko; Shibata, Yukio

doi:10.1042/bj2270537

Cited by 18 publications

(9 citation statements)

References 37 publications

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“…Additionally, XA might perpetuate P5P deficiency by inhibiting pyridoxal kinase, the enzyme catalyzing the formation of P5P from vitamin B6 [21]. …”

Section: Pyridoxal 5′-phosphate and Kyn – Nad Metabolic Pathwaymentioning

confidence: 99%

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

2013

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Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders (AAMPD). Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of literature and our data presents the evidences that dysregulation of tryptophan (TRP) – kynurenine (KYN) and KYN – nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. First and rate-limiting step of TRP – KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN – NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a co-factor. Deficiency of P5P diverts KYN – NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced up-regulation of TRP – KYN metabolism in combination with P5P deficiency-induced diversion of KYN – NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects-at-risk for IR. Pharmacological regulation of the TRP – KYN and KYN – NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress–induced excessive production of KYN and deficiency of vitamin B6, e.g., diabetes type 2, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.

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“…Additionally, XA might perpetuate P5P deficiency by inhibiting pyridoxal kinase, the enzyme catalyzing the formation of P5P from vitamin B6 [21]. …”

Section: Pyridoxal 5′-phosphate and Kyn – Nad Metabolic Pathwaymentioning

confidence: 99%

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

2013

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“…Instead, it appears that estrogens directly affect tryptophan metabolism (7). Another complication in tryptophan load experiments might be that several tryptophan metabolites inhibit pyridoxal kinase and activate pyridoxine 5' -phosphate oxidase (161). Miller (108) recommends monitoring the vitamin B6 status of women using these drugs.…”

Section: Pregnancy Lactation and Oral Contraceptivesmentioning

confidence: 99%

Diseases Associated with Defects in Vitamin B6 Metabolism or Utilization

Merrill¹,

Henderson²

1987

Annu. Rev. Nutr.

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“…Additionally, 3H-KYNA might perpetuate P5P defi ciency by inhibiting pyridoxal kinase, the enzyme catalyzing the formation of P5P from vitamin B 6 (Takeuchi et al 1985 ) Clinical and experimental studies indicate that P5P defi ciency combined with upregulated TRP conversion to KYN leads to increased availability of 3-HK as substrate for formation of 3KYNA and 8-HQ and increased availability of KYN as substrate for KYNA and QA in the cerebellum, corpus striatum, frontal cortex, and pons/medulla (Guilarte and Wagner 1987 ), blood (Midttun et al 2011 ;Ciorba 2013 ) and pancreatic islets (Rogers and Evangelista 1985 ).…”

Section: Regulation Of Downstream Kyn Metabolic Pathwaysmentioning

confidence: 99%

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

Oxenkrug

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Aging, obesity, depression, Parkinson's and other neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs are highly associated with insulin resistance (IR) and type 2 diabetes mellitus (T2D). Molecular mechanisms of increased associations remain uncertain. Current review of literature and our data suggest that one such mechanism is the overproduction of diabetogenic factors resulting from dysregulation of upstream and downstream pathways of tryptophan (TRP)-kynurenine (KYN) metabolism. Proinfl ammatory factors and stress hormones activate two upstream steps of TRP-KYN pathway: TRP conversion into KYN, a substrate for formation of kynurenic acid (KYNA), and KYN conversion into 3-hydroxyKYN (3-HK). The fi rst step of downstream pathway of 3-HK metabolism, formation of 3-hydroxyanthranilic acid (3-HAA), is catalyzed by pyridoxal-5-phosphate (P5P)-dependent kynureninase (KYNase). P5P defi ciency, associated with infl ammation, stress, and treatment with antipsychotic drugs, diverts metabolism of overproduced 3-HK from formation of 3-HAA to the excessive formation of 3-hydroxykynurenic acid (3H-KYNA). Human and experimental studies suggested diabetogenic (e.g., impairment of production, release, and biological activity of insulin) effect of KYN, 3H-KYNA, KYNA, and their metabolites. We propose that one of the mechanisms of increased association of IR (and T2D) with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs is overproduction of 3H-KYNA resulting from upregulated formation of 3-HK augmented by P5P defi ciency. Pharmacological regulation of upand downstream TRP-KYN metabolic pathways might be a new approach for prevention and treatment of IR (and IR progression to T2D) associated with aging, obesity, depression, neurodegenerative diseases, schizophrenia, and treatment with antipsychotic drugs.

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Effect of tryptophan metabolites on the activities of rat liver pyridoxal kinase and pyridoxamine 5-phosphate oxidase in vitro

Cited by 18 publications

References 37 publications

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

Insulin Resistance and Dysregulation of Tryptophan–Kynurenine and Kynurenine–Nicotinamide Adenine Dinucleotide Metabolic Pathways

Diseases Associated with Defects in Vitamin B6 Metabolism or Utilization

3-Hydroxykynurenic Acid and Type 2 Diabetes: Implications for Aging, Obesity, Depression, Parkinson’s Disease, and Schizophrenia

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