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S-adenosylmethionine and Pneumocystis carinii
S Merali1, D Vargas, M Franklin
1Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10010, USA. merals01@popmail.med.nyu.edu
The Journal of Biological Chemistry
|May 16, 2000
Summary
Pneumocystis carinii, an opportunistic fungal pathogen, absolutely requires S-adenosylmethionine (AdoMet) for growth. This study reveals P. carinii is an AdoMet auxotroph, making its uptake a target for new therapies.
Area of Science:
- Medical Mycology
- Molecular Biology
- Biochemistry
Background:
- Pneumocystis carinii is an opportunistic fungal pathogen associated with AIDS.
- S-adenosylmethionine (AdoMet) is crucial for methylation and polyamine biosynthesis.
- Previous work showed AdoMet enhances P. carinii axenic culture.
Purpose of the Study:
- To determine if AdoMet is essential for P. carinii continuous growth.
- To characterize the AdoMet uptake mechanism in P. carinii.
- To investigate potential chemotherapeutic targets related to AdoMet metabolism.
Main Methods:
- Axenic culture of P. carinii.
- Characterization of AdoMet transporters (affinity, pH optimum, competitive inhibition).
- Assessment of AdoMet uptake under various conditions (temperature, inhibitors).
- Measurement of AdoMet synthetase activity.
- Correlation analysis between rat AdoMet levels and P. carinii burden.
Main Results:
- AdoMet is absolutely required for continuous P. carinii growth.
- Two AdoMet transporters were identified: high-affinity (K(m)=4.5 µM) and low-affinity (K(m)=333 µM).
- High-affinity transport is active, pH-dependent (optimum 7.5), and relies on cytochrome and alternative oxidase pathways.
- P. carinii lacks detectable AdoMet synthetase activity.
- Rat AdoMet plasma concentration inversely correlates with lung P. carinii load.
Conclusions:
- Pneumocystis carinii is an S-adenosylmethionine (AdoMet) auxotroph.
- The characterized AdoMet uptake system represents a promising target for novel chemotherapeutic strategies against P. carinii infections.
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