The biochemistry of heme biosynthesis.

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.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/pro.405

Structure and function of enzymes in heme biosynthesis.

Higher plants produce four classes of tetrapyrroles, namely, chlorophyll (Chl), heme, siroheme, and phytochromobilin. In plants, tetrapyrroles play essential roles in a wide range of biological activities including photosynthesis, respiration and the assimilation of nitrogen/sulfur. All four classes of tetrapyrroles are derived from a common biosynthetic pathway that resides in the plastid. In this article, we present an overview of tetrapyrrole metabolism in Arabidopsis and other higher plants, and we describe all identified enzymatic steps involved in this metabolism. We also summarize recent findings on Chl biosynthesis and Chl breakdown. Recent advances in this field, in particular those on the genetic and biochemical analyses of novel enzymes, prompted us to redraw the tetrapyrrole metabolic pathways. In addition, we also summarize our current understanding on the regulatory mechanisms governing tetrapyrrole metabolism. The interactions of tetrapyrrole biosynthesis and other cellular processes including the plastid-to-nucleus signal transduction are discussed.

/pdf/tetrapyrrole-metabolism-in-arabidopsis-thaliana-3obk7jt4rj.pdf

Tetrapyrrole Metabolism in Arabidopsis thaliana.

The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized.

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product.

One of the most vigorous areas of photobiological research is concerned with the elucidation of the structure and biosynthesis of chlorophylls (Ch1s)t and bacteriochlorophylls (BChls) and their incorporation into pigment-protein complexes for both the harvesting and transduction of solar energy for photosynthesis. The keen interest in the formation of Chls and other natural tetrapyrrole pigments is reflected by the many recent reviews including Battersby and Leeper (I), Scheer ( 2 ) , Jordan (3), Deisenhofer and Noms (4), Senge (5 ) , Bryant (6), Chadwick and Ackrill (7), Blankenship et al. (8), Battersby (9) and Avissar and Moberg (10). This review concentrates on recent research papers in the field of Chl and BChl biosynthesis appearing since the last review on Chl in this journal in 1993 by Senge (5). An attempt is made to integrate this recent research on specific aspects of Chl biosynthesis into our understanding of the entire pathway. Much is known about the biosynthesis of the tetrapyrrole chromophores of Chls u and b, the major Chl-protein complexes of higher plants and algae; however, the biosyntheses of many of the Chls c of the chromophyte algae (1 1) and of many of the known BChls of the photosynthetic bacteria (2) still require investigation. Only partially understood, however, is the manner of the

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1997.tb08596.x

Recent Progress in Porphyrin and Chlorophyll Biosynthesis

The hepta-, hexa- and penta-carboxylic porphyrins found in the faeces of rats poisoned with hexachlorobenzene have been separated by high-pressure liquid chromatography and characterized largely by spectroscopie methods. Their structures were confirmed by total synthesis, as part of a programme in which eleven of the fourteen hepta-, hexa- and penta-carboxylic porphyrins derived from uroporphyrin III have now been synthesized as their methyl esters. The four isomeric heptacarboxylic and three of the pentacarboxylic porphyrinogens have been incubated with haemolysates of chicken erythrocytes, and they are all converted into protoporphyrin IX but at different rates. On the basis of this and other evidence we conclude that the decarboxylation of uroporphyrinogen III to coproporphyrinogen III is a stepwise process taking place by a preferred pathway (both in normal and abnormal metabolism); the acetic acid groups are decarboxylated in a sequential clockwise fashion starting with that on the D ring and followed by those on the A, B and C rings. In the poisoned rats the uroporphyrinogen decarboxylase enzyme (or group of enzymes) is probably partially inhibited and the pentacarboxylic porphyrinogen with an acetic acid group on ring C accumulates. The latter is then transformed by a side pathway into dehydroisocoproporphyrinogen and thence into dehydroisocoproporphyrin and its congeners.

Macrocyclic intermediates in the biosynthesis of porphyrins.

In the course of our studies on intermediates in normal and abnormal metabolism of porphyrins we have synthesised a number of porphyrins related to uroporphyrin-III and compared them with materials isolated from natural sources. In the present paper we show that the corresponding porphyrinogens are all metabolised to protoporphyrin-IX by haemolysates of chicken erythrocytes, but at different rates. The results are discussed in relation to our conclusions concerning the preferred pathway of degradation of uro'gen-III to coproporphyrinogen-III, which indicate a clockwise sequence of decarboxylation reactions.

Hepta- and hexa-carboxylic porphyrinogen intermediates in haem biosynthesis.

The incorporation of the four possible type III porphyrinogens into protoporphyrin is described and their various rates or conversion are discussed. The techniques used involved the incubation of the porphyrinogens in chicken red cell haemolysates followed by extraction and characterisation of the end products on HPLC and TLC. Porphyrin 5 b c d was shown to be more slowly incorporated than porphyrins 5 a b d, 5 a c d and 5 a b c. The relevance of these findings to an understanding of the porphyrin excretion pattern in hepato-erythrocitic porphyria is considered.

Ferramola Am

Papers

Macrocyclic intermediates in the biosynthesis of porphyrins.

Hepta- and hexa-carboxylic porphyrinogen intermediates in haem biosynthesis.

Pentacarboxylic intermediates in haem biosynthesis.