From B to A: making an essential cofactor in a human parasite

Area of Science:

• Parasitology
• Biochemistry
• Molecular Biology

Background:

• Trypanosomatids are parasitic eukaryotes with complex life cycles, alternating between hosts and morphologies.
• Unlike most organisms, they cannot synthesize heme, an essential cofactor, and must acquire it from hosts.
• They convert acquired heme B to heme A, used exclusively by cytochrome c oxidase (CcO).

Purpose of the Study:

• To investigate the role of heme A synthesis and CcO activity in the infectivity and replication of Trypanosoma cruzi.
• To elucidate the essentiality of the final heme A biosynthesis step and CcO function in this parasite.

Main Methods:

• Enzyme assays to study heme A synthesis by heme A synthase (TcCox15).
• Analysis of cytochrome c oxidase (CcO) activity.
• Assessment of parasite infectivity and replication in host models.

Main Results:

• The final step in heme A synthesis, catalyzed by TcCox15, is essential.
• The activity of cytochrome c oxidase (CcO), which utilizes heme A, is also critical.
• Disruption of these processes significantly impairs Trypanosoma cruzi infectivity and replication.

Conclusions:

• Heme A biosynthesis and CcO function are indispensable for Trypanosoma cruzi infectivity and replication.
• Targeting heme A synthesis or CcO activity presents a potential strategy for treating Chagas disease.