Back to Search
Start Over
Multiple roles of haem in cystathionine β-synthase activity: implications for hemin and other therapies of acute hepatic porphyria
- Source :
- Bioscience Reports
- Publication Year :
- 2021
- Publisher :
- Portland Press Ltd., 2021.
-
Abstract
- The role of haem in the activity of cystathionine β-synthase (CBS) is reviewed and a hypothesis postulating multiple effects of haem on enzyme activity under conditions of haem excess or deficiency is proposed, with implications for some therapies of acute hepatic porphyrias. CBS utilises both haem and pyridoxal 5′-phosphate (PLP) as cofactors. Although haem does not participate directly in the catalytic process, it is vital for PLP binding to the enzyme and potentially also for CBS stability. Haem deficiency can therefore undermine CBS activity by impairing PLP binding and facilitating CBS degradation. Excess haem can also impair CBS activity by inhibiting it via CO resulting from haem induction of haem oxygenase 1 (HO 1), and by induction of a functional vitamin B6 deficiency following activation of hepatic tryptophan 2,3-dioxygenase (TDO) and subsequent utilisation of PLP by enhanced kynurenine aminotransferase (KAT) and kynureninase (Kynase) activities. CBS inhibition results in accumulation of the cardiovascular risk factor homocysteine (Hcy) and evidence is emerging for plasma Hcy elevation in patients with acute hepatic porphyrias. Decreased CBS activity may also induce a proinflammatory state, inhibit expression of haem oxygenase and activate the extrahepatic kynurenine pathway (KP) thereby further contributing to the Hcy elevation. The hypothesis predicts likely changes in CBS activity and plasma Hcy levels in untreated hepatic porphyria patients and in those receiving hemin or certain gene-based therapies. In the present review, these aspects are discussed, means of testing the hypothesis in preclinical experimental settings and porphyric patients are suggested and potential nutritional and other therapies are proposed.
- Subjects :
- 0301 basic medicine
Kynurenine pathway
Homocysteine
3-Hydroxykynurenine
Pharmacology
Biochemistry
chemistry.chemical_compound
Kynureninase
0302 clinical medicine
polycyclic compounds
Carbon monoxide
Review Articles
Diagnostics & Biomarkers
Kynurenine
biology
Pharmacology & Toxicology
digestive, oral, and skin physiology
Tryptophan
Treatment Outcome
Vitamin B Complex
Hemin
congenital, hereditary, and neonatal diseases and abnormalities
Biophysics
Cystathionine beta-Synthase
Nutritional Status
Heme
Hepatic porphyria
03 medical and health sciences
Biochemical Techniques & Resources
Xanthurenic acid
Acute intermittent porphyria
Animals
Humans
Pyridoxal 5′-phosphate
Molecular Biology
Pyridoxal
nutritional and metabolic diseases
Cell Biology
Cystathionine beta synthase
Porphyrias, Hepatic
Metabolism
030104 developmental biology
chemistry
Enzymology
biology.protein
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15734935 and 01448463
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Bioscience Reports
- Accession number :
- edsair.doi.dedup.....cb9290c47c2028f6b3c34d6317ea7500
- Full Text :
- https://doi.org/10.1042/bsr20210935