Award details

Identification and characterization of the c-type cytochrome biogenesis apparatus of trypanosomes and the Euglenozoa

Reference	BB/D019753/1
Principal Investigator / Supervisor	Dr James Allen
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Biochemistry
Funding type	Research
Value (£)	550,781
Status	Completed
Type	Fellowships
Start date	01/10/2006
End date	30/09/2011
Duration	60 months

Abstract

The c-type cytochromes are distinguished by the covalent binding of heme to the polypeptide via thioether bonds. This chemically difficult heme attachment reaction requires a post-translational apparatus in the cell. There are three known systems for this: System I (occurring in Gram-negative bacteria and plant mitochondria), System II (occurring in Gram-positive bacteria and photosynthetic organelles) and System III (occurring in fungal and mammalian mitochondria). Surprisingly however, there is no sign of any of these systems in the recently completed genome sequences of six trypanosomatid species. This implies that there is a System IV, a view that correlates intriguingly with the fact that in this class of organism the heme is, uniquely, attached to the cytochrome c polypeptide via just one thioether bond rather than the normal two. A multi-disciplinary approach will be applied to identifying and subsequently characterizing the biosynthesis apparatus for c-type cytochromes in the medically important trypanosomes.

Summary

Proteins are a major component of all living cells. They are nature's molecular machines and include enzymes, natural catalysts of chemical reactions. In addition to the basic amino acid building blocks, one-third of all proteins contain one or more metal ions (e.g. iron, zinc, copper), found singly, in metal clusters, or bound within a larger molecule and then to the protein. These metals in proteins provide excellent and elegantly tuned centres for nature to catalyse diverse chemical reactions; the reactions they facilitate are crucial for the life of all organisms. Respiration is the fundamental cellular process by which the fuel organisms consume (i.e. food) reacts with the oxygen they take in (e.g. by breathing) to produce the energy their cells need in a biologically useful form. An essential protein for respiration is called cytochrome c; it contains the molecule heme, which has an iron atom bound at its centre. Heme is the pigment that carries oxygen around our bodies when bound to the blood protein hemoglobin. However, unlike in hemoglobin, the heme in cytochrome c is attached permanently to the protein through (normally) two covalent bonds. Remarkably, at least three different systems have evolved in different types of organisms to accomplish this unusual and chemically difficult covalent heme attachment reaction. Understanding how these systems work and why different ones have evolved is a problem with wide ranging implications. As a consequence of some experiments I did on cytochrome c assembly in bacteria, I began to consider a family of single-celled organisms called trypanosomes. These are parasites of humans, animals and insects and cause fatal insect-bite transmitted diseases including African sleeping sickness, Chagas disease and Leishmaniasis, which threaten millions of people. Trypanosome cells contain cytochrome c which is special, because the heme is, uniquely, attached to the protein through only one covalent bond, rather than the usual two; this cytochrome c is required for the growth and survival of the cells. Recently, the genomes of six trypanosome species have been analysed. A genome is the blueprint of a species encoded by its DNA; it tells us all the proteins that the organism can make. Very surprisingly, the trypanosome genomes contain none of the proteins associated with the formation of cytochrome c in any other organisms. My project will be to answer questions related to these intriguing observations, principally: (i) What is the novel, completely unknown, system for making cytochrome c in these organisms? and (ii) How does the system work? I will use a wide range of experimental methods to address these questions. This work will be undertaken at the University of Oxford, using the world-class facilities for trypanosome research at the Dunn School of Pathology and for cytochrome research in the Department of Biochemistry. This exceptional conjunction of facilities makes Oxford a centre of excellence for this project. The discovery and characterization of a completely novel type of cytochrome c biogenesis system in the trypanosomes will be important. Fundamentally, it is necessary to establish how living cells carry out the individual processes they need for survival as scientists strive to understand how whole cells (and whole organisms) function. The novel means of cytochrome c synthesis used by the trypanosomes will also provide information about the uncertain evolutionary development of these specialized organisms, which is critical for understanding their biology. More specifically, cytochrome c formation in these infectious species is clearly distinct from that in mammals and so is a possible target for therapeutic drugs for humans and animals.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Animal Health, Microbiology
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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