Biosynthesis of porphyrins and related macrocycles. Part VI. Nature of the rearrangement process leading to the natural type III porphyrins

Battersby, Alan R.; Hodgson, Gordon L.; Hunt, Eric; McDonald, Edward; Saunders, John

doi:10.1039/p19760000273

Cited by 36 publications

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“…It was found around 1980 in a series of studies using labeled PBG, that first a linear tetrapyrrole is formed followed by ring closure with rearrangement of ring D 99, 100. At that time it was also observed that the oligomerization of PBG starts with ring A followed by rings B, C, and D 101, 102.…”

Section: Structures and Mechanisms Of Heme Biosynthetic Enzymesmentioning

confidence: 99%

Structure and function of enzymes in heme biosynthesis

et al. 2010

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Tetrapyrroles like hemes, chlorophylls, and cobalamin are complex macrocycles which play essential roles in almost all living organisms. Heme serves as prosthetic group of many proteins involved in fundamental biological processes like respiration, photosynthesis, and the metabolism and transport of oxygen. Further, enzymes such as catalases, peroxidases, or cytochromes P450 rely on heme as essential cofactors. Heme is synthesized in most organisms via a highly conserved biosynthetic route. In humans, defects in heme biosynthesis lead to severe metabolic disorders called porphyrias. The elucidation of the 3D structures for all heme biosynthetic enzymes over the last decade provided new insights into their function and elucidated the structural basis of many known diseases. In terms of structure and function several rather unique proteins were revealed such as the V-shaped glutamyl-tRNA reductase, the dipyrromethane cofactor containing porphobilinogen deaminase, or the ''Radical SAM enzyme'' coproporphyrinogen III dehydrogenase. This review summarizes the current understanding of the structure-function relationship for all heme biosynthetic enzymes and their potential interactions in the cell.

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Section: Structures and Mechanisms Of Heme Biosynthetic Enzymesmentioning

confidence: 99%

Structure and function of enzymes in heme biosynthesis

et al. 2010

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“…(a) Preparation of heat-treated enzyme. Euglena gracilis was grown and harvested as described by Battersby et al (1976a). Frozen cells (approx.…”

Section: Purification Ofporphobilinogen Deaminasementioning

confidence: 99%

Purification of porphobilinogen deaminase from Euglena gracilis and studies of its kinetics

Williams¹,

Morgan²,

McDonald³

et al. 1981

Biochemical Journal

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1. Porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] from Euglena gracilis was purified more than 200-fold. 2. The enzyme has a molecular weight of 41 000 +/- 2000, does not contain a chromophoric prosthetic group, and appears not to require metal ions for activity. 3. The stoicheiometry of the overall reaction at pH 7.4 was shown to be: 4 Porphobilinogen leads to uroporphyrinogen-I + 4 NH4+. This stoicheiometry for porphobilinogen and uroporphyrinogen was also observed over a wide range of pH values. 4. Initial-velocity studies showed a hyperbolic dependence of velocity on substrate concentration, demonstrating the existence of a displacement-type mechanism. 5. Vmax. varied with pH as a typical bell-shaped curve, indicating that two ionizable groups with pK values of 6.1 and 8.9 are important for catalysis. A plot of Vmax./Km against pH showed a single ionization (pK 8.2) to influence binding of substrate.

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“…The mechanism of this inversion was investigated extensively by Battersby and co‐workers using chemically synthesized analogues of the substrate and intermediate. They demonstrated formation of a spirocyclic pyrrolenine intermediate in the course of the D ring flip and proposed the reaction scheme (Battersby et al , , ; Leeper, ). This mechanism has been supported by high‐level quantum mechanical calculations on model systems of this enzyme (Silva & Ramos, ).…”

Section: Biochemical Backgroundmentioning

confidence: 99%

Advances in understanding the pathogenesis of congenital erythropoietic porphyria

2016

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Congenital erythropoietic porphyria (CEP) is a rare genetic disease resulting from the remarkable deficient activity of uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. This enzyme defect results in overproduction of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I. The predominant clinical characteristics of CEP include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. The severity of clinical manifestations is markedly heterogeneous among patients; and interdependence between disease severity and porphyrin amount in the tissues has been pointed out. A more pronounced endogenous production of porphyrins concomitant to activation of ALAS2, the first and rate-limiting of the haem synthesis enzymes in erythroid cells, has also been reported. CEP is inherited as autosomal recessive or X-linked trait due to mutations in UROS or GATA1 genes; however an involvement of other causative or modifier genes cannot be ruled out.

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Biosynthesis of porphyrins and related macrocycles. Part VI. Nature of the rearrangement process leading to the natural type III porphyrins

Abstract: PorPhYrinogen (5) to (6)* phPin-IX ( ' 1 produced enzpically four bridges gave four separate 13C n.m.r. signals. labelled PBG also holds true for uroporphyrinogen-I11 Earlier work had shown that the dimethyl ester of , .

Cited by 36 publications

References 0 publications

Structure and function of enzymes in heme biosynthesis

Structure and function of enzymes in heme biosynthesis

Purification of porphobilinogen deaminase from Euglena gracilis and studies of its kinetics

Advances in understanding the pathogenesis of congenital erythropoietic porphyria

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