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Brain Therapy

Animals administered an FKBP38-specific inhibitor (N-(N',N'-dimethylcarboxamidomethyl)cycloheximide (DM-CHX)) exhibited neurogenesis.

The immunosuppressive drug FK506 reversibly inhibits members of the FK506-binding protein (FKBP) family of peptidylprolyl cis/trans-isomerases. Interestingly, FK506 and its open chain derivatives also demonstrate neuroprotective and neuroregenerative effects in a wide range of animal models mimicking Parkinson disease, dementia, stroke, and nerve damage. However, the molecular mechanism of these FK506-mediated effects remains elusive.

Now, Frank Edlich and colleagues shed some light on this issue by showing that these neurotrophic FKBP ligands specifically target FKBP38. This isomerase is different from the other members of the FKBP family in that it is only active when bound to calmodulin/Ca²⁺. Edlich et al. synthesized an FKBP38-specific inhibitor and used it in a rat model of transient focal cerebral ischemia. They found that the ligand caused neuronal protection as well as neural stem cell proliferation and neuronal differentiation. Diseased animals with sustained motor behavior deficits also showed improvement when administered the drug, hinting at its potential therapeutic application. Not only does this manuscript present a beautiful synthesis of biochemistry, molecular pharmacology, and experimental medicine, it also provides a possible strategy for the treatment of acute and/or chronic neurodegenerative diseases.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 14961-14970

CORroborating Chlorin B-ring Reduction

Two sequential reactions are catalyzed by DPOR and COR in bacteriochlorophyll a biosynthesis.

Bacteriochlorophyll a is a photosynthetic pigment found in purple bacteria that both harvests light and drives the photosynthetic electron transfer in the reaction center. Biosynthesis of this pigment is a multistep process, the final stages of which involve the reduction of the porphyrin D-ring by the dark-operative nitrogenase-like protochlorophyllide reductase (DPOR) to form the chlorin ring. Subsequently, the chlorin B-ring is reduced to form a bacteriochlorin ring structure. Although studies have suggested that this second reaction is carried out by another nitrogenase-like enzyme, there is no biochemical evidence for this.

In this Paper of the Week, Jiro Nomata and colleagues describe the purification and initial characterization of chlorophyllide a reductase (COR), the enzyme system that catalyzes the reduction of the chlorin B-ring. The authors succeed in purifying the two components of this enzyme, the ATPase/reductase subunit (BchX) and the presumptive active site-bearing BchY-BchZ component. The enzyme activity, as anticipated based upon analogy to DPOR and nitrogenase, requires reductant (dithionite) and ATP. The description of this important and novel enzyme demonstrates that the sequential actions of two nitrogenase-like enzymes, DPOR and COR, convert porphyrin to bacteriochlorin.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 15021-15028

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