Quantitative Structural Insight into Human Variegate Porphyria Disease

Wang, Baifan; Wen, Xin; Qin, Xinghu; Wang, Zhifang; Tan, Ying; Shen, Yuequan; Xi, Zhen

doi:10.1074/jbc.m113.459768

Cited by 42 publications

(55 citation statements)

References 48 publications

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“…One example includes mutations in the human protoporphyrinogen oxidase (hPPO) gene which are responsible for the dominantly inherited disorder variegate porphyria (VP). Two missense mutations (R59Q and R59G) were investigated in a recent work 130 where MD modeling revealed that these mutations affect the catalytic activity of hPPO by changing its ability to sample different conformations. Analysis of mutation H101Q in the CLIC2 protein demonstrated that this mutation restricted the mobility of the N-terminal domain and prevented the conformational change presumed to be required for entering of CLIC2 into the membrane.…”

Section: Effect Of Mutations On Conformational Dynamicsmentioning

confidence: 99%

Molecular Mechanisms of Disease-Causing Missense Mutations

Stefl

Nishi

Petukh

et al. 2013

Journal of Molecular Biology

268

229

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Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions, and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies which illustrate the association between missense mutations and diseases. In addition we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally we report the current state-of-the-art methodologies which predict the effects of mutations on protein stability, the hydrogen bond network, pH-dependence, conformational dynamics and protein function.

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Section: Effect Of Mutations On Conformational Dynamicsmentioning

confidence: 99%

Molecular Mechanisms of Disease-Causing Missense Mutations

Stefl

Nishi

Petukh

et al. 2013

Journal of Molecular Biology

268

229

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“…Unfortunately, there are no crystal structures with a bound substrate or product that would help to identify essential interactions between the tetrapyrrole and the enzyme. However, there are structures with a bound inhibitor, which allowed in silico modeling of substrate binding (210)(211)(212)264). Based upon kinetic studies with a tritium-labeled substrate, it was proposed that three meso-carbon hydride ions are removed from the same surface of the tetrapyrrole in a sequential fashion with the concomitant removal of the NH proton (265).…”

Section: Prokaryotic Heme Biosynthesismentioning

confidence: 99%

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Dailey

Gerdes³

et al. 2017

Microbiol Mol Biol Rev

260

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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“…The result provided structural evidence for protogen IX binding place in PPO. Therefore, we have explored the binding mode of protogen IX in h PPO through molecular simulation and site‐directed mutagenesis study ,. Interestingly, the binding mode of protogen IX in h PPO was different from the one in mt PPO proposed by Koch et al ., which showed the methylene bridge atom C5, instead of C20 (see Scheme ), was close to the N5 atom of FAD.…”

Section: Methodsmentioning

confidence: 93%

Molecular Simulations Bring New Insights into Protoporphyrinogen IX Oxidase/Protoporphyrinogen IX Interaction Modes

Wang

Wen

2016

Molecular Informatics

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Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) catalyzes the oxidation of protoporphyrinogen IX (protogen IX) to protoporphyrin IX (proto IX) in the haem/chlorophyll biosynthetic pathway. Although extensive studies of PPO have already afforded many insights into its biological function and its significance to agriculture and medicine, details of the enzymatic mechanism as well as the nature of the specific amino acids involved in substrate binding still remain largely unknown due to the lack of structural information about protogen IX binding to PPO. In this study, we carried out a detailed and systematic investigation on the binding mode of protogen IX in the Nicotiana tabacum PPO (mtPPO) by performing a computational docking followed by molecular simulations, quantum mechanics calculations, and an integrated analysis. The proposed binding mode was consistent with experimental studies, and several potential key residues that have not been investigated in previous studies, such as Thr70, Arg233, Ser235, Ser474 and Lys477, were identified. In addition, we compared the binding modes of protogen IX in mtPPO and Homo sapiens PPO, and found their differences. Considering the low sequence identity and the differences of biochemical properties among the PPOs from various species, the investigation could provide a valuable basis for the design of PPO inhibitors with high potency and species-selectivity.

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Quantitative Structural Insight into Human Variegate Porphyria Disease

Cited by 42 publications

References 48 publications

Molecular Mechanisms of Disease-Causing Missense Mutations

Molecular Mechanisms of Disease-Causing Missense Mutations

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Molecular Simulations Bring New Insights into Protoporphyrinogen IX Oxidase/Protoporphyrinogen IX Interaction Modes

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