Crystal structure of protoporphyrinogen IX oxidase: a key enzyme in haem and chlorophyll biosynthesis
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Protoporphyrinogen IX oxidase (PPO), the last common enzyme of haem and chlorophyll biosynthesis, catalyses the oxidation of protoporphyrinogen IX to protoporphyrin IX. The membrane-embedded flavoprotein is the target of a large class of herbicides. In humans, a defect in PPO is responsible for the dominantly inherited disease variegate porphyria. Here we present the crystal structure of mitochondrial PPO from tobacco complexed with a phenyl-pyrazol inhibitor. PPO forms a loosely associated dimer and folds into an FAD-binding domain of the p-hydroxybenzoate-hydrolase fold and a substrate-binding domain that enclose a narrow active site cavity beneath the FAD and an alpha-helical membrane-binding domain. The active site architecture suggests a specific substrate-binding mode compatible with the unusual six-electron oxidation. The membrane-binding domains can be docked onto the dimeric structure of human ferrochelatase, the next enzyme in haem biosynthesis, embedded in the opposite side of the membrane. This modelled transmembrane complex provides a structural explanation for the uncoupling of haem biosynthesis observed in variegate porphyria patients and in plants after inhibiting PPO.
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PpIX is synthesized in mitochondria and requires FAD-containing protoporphyrinogen oxidase (PPO).
“The next intermediate in heme biosynthesis, protoporphyrin IX (PpIX), is synthesized in the mitochondria and requires FAD-containing protoporphyrinogen oxidase (PPO) [24,25].”
From Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer (2011) · cites this paper as [25]
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- Authors
- Koch, M., Breithaupt, C., Kiefersauer, R., Freigang, J., Huber, R., & Messerschmidt, A.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- Bayer (Germany) (DE)
- Corresponding author
- Koch, Michael
- Messerschmidt, Albrecht
- Venue
- The EMBO Journal
- Published
- 2004-04-01
- Volume
- 23
- Issue
- 8
- Pages
- 1720-1728
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC394243
- OpenAlex
- W2064050113
- Cited by
- 299
- References
- 33
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 17 · 2023: 20 · 2022: 9 · 2021: 12 · 2020: 8 · 2019: 27 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 11 · 2014: 12 · 2013: 11 · 2012: 10
- FWCI
- 3.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- European Synchrotron Radiation Facility
- Bayer CropScience
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Porphyrin Metabolism and Disorders
- Physical Sciences › Materials Science › Materials Chemistry › Porphyrin and Phthalocyanine Chemistry
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- protoporphyrinogen IX oxidase, heme biosynthesis, chlorophyll biosynthesis, variegate porphyria, flavoprotein, FAD-binding domain, membrane-binding domain, ferrochelatase, herbicide targets, tobacco, crystal structure
- MeSH terms
- Amino Acid Sequence, Binding Sites, Catalysis, Cell Membrane, Chlorophyll, Ferrochelatase, Flavoproteins, Heme, Humans, Mitochondria, Models, Molecular, Molecular Sequence Data, Nicotiana, Sequence Alignment, Crystallography, X-Ray, Dimerization, Protein Structure, Quaternary, Protein Subunits, Mitochondrial Proteins, Oxidoreductases Acting on CH-CH Group Donors, Porphyria, Variegate, Protoporphyrinogen Oxidase
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