Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate. Cystathionine beta-synthase is a heme protein.

Kéry, Vladimír; Bukovská, Gabriela; Kraus, Jan P.

doi:10.1016/s0021-9258(18)47244-4

Cited by 165 publications

(79 citation statements)

References 28 publications

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“…Deficient CBS enzymatic activity caused by reduction of the heme hepatic pool by givosiran targeting of ALAS1 mRNA is the logical main hypothesis to explain the aggravated phenotype. The N-terminus part of the CBS enzyme contains a heme-binding motif, 31 thus, enzyme activity could be hypothetically sensitive to hepatic heme reduction. 31 The role of the heme-binding motif in CBS is, however, not fully understood, since it is not directly involved in the catalysis, but it may still influence the folding of the enzyme and being sensitive to the redox status of its environment, as comprehensively reviewed in Zuhra et al 32 There are few studies exploring the effect of givosiran on heme status in the liver.…”

Section: Hcy Regulation In Recurrent Aip Patients On Givosiran Treatmentmentioning

confidence: 99%

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran

To‐Figueras

Wijngaard

García‐Villoria

et al. 2021

J of Inher Metab Disea

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Acute intermittent porphyria (AIP) is a rare metabolic disease caused by mutations within the hydroxymethylbilane synthase gene. Previous studies have reported increased levels of plasma total homocysteine (tHcy) in symptomatic AIP patients.In this study, we present long-term data for tHcy and related parameters for an AIP patient cohort (n = 37) in different clinical disease-states. In total, 25 patients (68%) presented with hyperhomocysteinemia (HHcy; tHcy > 15 μmol/L) during the observation period. HHcy was more frequent in AIP patients with recurrent disease receiving heme arginate, than in nonrecurrent (median tHcy: 21.6 μmol/L; range: 10-129 vs median tHcy: 14.5 μmol/L; range 6-77). Long-term serial analyses showed a high within-person tHcy variation, especially among the recurrent patients (coefficient of variation: 16.4%-78.8%). HHcy was frequently associated with low blood concentrations of pyridoxal-5 0 -phosphate and folate, while cobalamin concentration and the allele distribution of the methylene-tetrahydrofolatereductase gene were normal. Strikingly, 6 out of the 9 recurrent patients who were later included in a regime of givosiran, a small-interfering RNA that effectively reduced recurrent attacks, showed further increased tHcy (median tHcy in 9 patients: 105 μmol/L; range 16-212). Screening of amino acids in plasma by liquid-chromatography showed co-increased levels of methionine (median 71 μmol/L; range 23-616; normal <40), suggestive of acquired deficiency of cystathionine-β-synthase. The kynunerine/tryptophan ratio in plasma was, however, normal, indicating a regular metabolism of tryptophan by heme-dependent enzymes. In conclusion, even if HHcy was observed in AIP patients receiving heme arginate, givosiran induced an aggravation of the dysregulation, causing a coincrease of tHcy and methionine resembling classic homocystinuria.

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Section: Hcy Regulation In Recurrent Aip Patients On Givosiran Treatmentmentioning

confidence: 99%

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran

To‐Figueras

Wijngaard

García‐Villoria

et al. 2021

J of Inher Metab Disea

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“…CBS is a pyridoxal 5 -phosphate (PLP) enzyme that catalyzes the transsulfuration pathway to convert homocysteine (Hcy) and serine into cystathionine and regulates hydrogen sulfide (H2S) metabolism [185][186][187]. It is a heme protein that conducts critical cellular bioenergetic-related processes, such as redox regulation [188] and mitochondrial homeostasis [189].…”

Section: Cbsmentioning

confidence: 99%

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

Wang

Ashrafi

Modareszadeh

et al. 2021

Cancers

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Heme is an essential prosthetic group in proteins and enzymes involved in oxygen utilization and metabolism. Heme also plays versatile and fascinating roles in regulating fundamental biological processes, ranging from aerobic respiration to drug metabolism. Increasing experimental and epidemiological data have shown that altered heme homeostasis accelerates the development and progression of common diseases, including various cancers, diabetes, vascular diseases, and Alzheimer’s disease. The effects of heme on the pathogenesis of these diseases may be mediated via its action on various cellular signaling and regulatory proteins, as well as its function in cellular bioenergetics, specifically, oxidative phosphorylation (OXPHOS). Elevated heme levels in cancer cells intensify OXPHOS, leading to higher ATP generation and fueling tumorigenic functions. In contrast, lowered heme levels in neurons may reduce OXPHOS, leading to defects in bioenergetics and causing neurological deficits. Further, heme has been shown to modulate the activities of diverse cellular proteins influencing disease pathogenesis. These include BTB and CNC homology 1 (BACH1), tumor suppressor P53 protein, progesterone receptor membrane component 1 protein (PGRMC1), cystathionine-β-synthase (CBS), soluble guanylate cyclase (sGC), and nitric oxide synthases (NOS). This review provides an in-depth analysis of heme function in influencing diverse molecular and cellular processes germane to disease pathogenesis and the modes by which heme modulates the activities of cellular proteins involved in the development of cancer and other common diseases.

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“…Πρόσφατες εργασίες υποδεικνύουν την ύπαρξη και ενός άλλου ρυθμιστικού μηχανισμού ευαίσθητου στο οξειδωτικό stress. Η συνθάση της κυσταθειόνης, μια πρωτεΐνη της αίμης [300] είναι ενεργός στην οξειδωμένη μορφή της [301]. Αντιθέτως, η συνθάση της μεθειονίνης με την οξείδωση απενεργοποιείται και απαιτεί μεθυλίωση αναγωγής για να επανεργοποιηθεί [302].…”

Section: εικόνα 10 η δομή της ομοκυστεΐνης (Hcy)unclassified

Ρόλος Νευρομεταβιβαστικών Αμινοξέων Στην Παθοφυσιολογία Του Γλαυκώματος Ανοικτής Γωνίας

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Transsulfuration depends on heme in addition to pyridoxal 5'-phosphate. Cystathionine beta-synthase is a heme protein.

Cited by 165 publications

References 28 publications

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran

Dysregulation of homocysteine homeostasis in acute intermittent porphyria patients receiving heme arginate or givosiran

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

Ρόλος Νευρομεταβιβαστικών Αμινοξέων Στην Παθοφυσιολογία Του Γλαυκώματος Ανοικτής Γωνίας

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