Role of aspartate 400, arginine 262, and arginine 401 in the catalytic mechanism of human coproporphyrinogen oxidase

Stephenson, Jason R.; Stacey, Julie; Morgenthaler, Justin B.; Friesen, Jon A.; Lash, Timothy D.; Jones, Marjorie A.

doi:10.1110/ps.062636907

Cited by 19 publications

(16 citation statements)

References 31 publications

(48 reference statements)

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“…A conserved aspartate residue in the active site was identified and suggested to be the initial base for catalysis. In addition, two conserved arginine residues were proposed to form hydrogen bonds with propionate side chains of the pyrrole rings so as to properly orient the substrate in the active-site pocket (249)(250)(251). genetic approaches were necessary to identify the corresponding cgdH gene and allow recombinant production of the E. coli enzyme, its detailed biochemical characterization, and determination of its crystal structure (255-260) (PDB accession number 1OLT).…”

Section: Conversion Of Coproporphyrinogen III Into Protoporphyrinogenmentioning

confidence: 99%

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Dailey

Gerdes³

et al. 2017

Microbiol Mol Biol Rev

265

335

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SUMMARY 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.

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Section: Conversion Of Coproporphyrinogen III Into Protoporphyrinogenmentioning

confidence: 99%

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Dailey

Gerdes³

et al. 2017

Microbiol Mol Biol Rev

265

335

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“…Unfortunately, the two solved crystal structures for CPO did not contain substrate or product precluding a precise assignment of amino acid residues directly involved in catalysis 127, 128. However, in a recent biochemical study employing mutant human CPOs it was suggested that a highly conserved aspartate residue might serve as the base for NH proton abstraction, and two conserved arginine residues were proposed to coordinate the substrate carboxylate groups 163…”

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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“…In every case, the narrow confines of the substrate-binding crevice prevent the substrate from assuming the "domed" conformation postulated previously 12,19 , and impose a chair/chaise longue conformation instead. Unless otherwise noted, the distances mentioned in these descriptions are measured between the terminal carbon of methyl (or propionate) pyrrole substituents and Cγ (Asp residues), Cε (Arg/His residues), sidechain O (Thr/Ser residues), sidechain N (Asn residues) or closest carbon atom (all other residues) and averaged from simulation snapshots taken at 7.5 ps intervals from 500-10500 ps.…”

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confidence: 80%

Computational Characterization of the Substrate-Binding Mode in Coproporphyrinogen III Oxidase

Silva

Ramos

2011

J. Phys. Chem. B

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Abstract:Oxygen-dependent coproporphyrinogen III oxidase catalyzes the sequential decarboxylation of the propionate substituents present on the A and B rings of coproporphyrinogen III in the heme biosynthetic pathway. Although extensive experimental investigation of this enzyme has already afforded many insights on its reaction mechanism, several key features (such as the substrate binding mode, the characterization of the active site and the initial substrate protonation state) remain poorly described. The molecular dynamics simulations described in this paper enabled the determination of a very promising substrate binding mode and the extensive characterization of the enzyme active site. The proposed binding mode is fully consistent with the known selectivity of the active site towards substituted tetrapyrroles, and explains the lack of activity of the H131A, R135A, D274A and R275A mutants and the reasons behind the non-occurrence of catalysis on the C and D rings of the tetrapyrrole.An important role in this binding mode is fulfilled by G276, as its carbonyl oxygen intervenes in the substrate anchoring by hydrogen-bonding its ring D pyrrole NH group. The presence of this interaction (which is only possible with protonated NH pyrrole group), and the absence of positively-charged side chains close to the pyrrole nitrogen (which might stabilize the N-deprotonated pyrrole postulated in some mechanistic proposals) shows that the pyrrole ring is very unlikely to undergo deprotonation during the catalytic cycle and allow the discrimination between the previously postulated mechanistic proposals.

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Role of aspartate 400, arginine 262, and arginine 401 in the catalytic mechanism of human coproporphyrinogen oxidase

Cited by 19 publications

References 31 publications

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Structure and function of enzymes in heme biosynthesis

Computational Characterization of the Substrate-Binding Mode in Coproporphyrinogen III Oxidase

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