PMID- 33947751
OWN - NLM
STAT- MEDLINE
DCOM- 20211013
LR  - 20211013
IS  - 2150-7511 (Electronic)
VI  - 12
IP  - 3
DP  - 2021 May 4
TI  - Divergent Cytochrome c Maturation System in Kinetoplastid Protists.
LID - 10.1128/mBio.00166-21 [doi]
LID - e00166-21
AB  - In eukaryotes, heme attachment through two thioether bonds to mitochondrial 
      cytochromes c and c(1) is catalyzed by either multisubunit cytochrome c 
      maturation system I or holocytochrome c synthetase (HCCS). The former was 
      inherited from the alphaproteobacterial progenitor of mitochondria; the latter is 
      a eukaryotic innovation for which prokaryotic ancestry is not evident. HCCS 
      provides one of a few exemplars of de novo protein innovation in eukaryotes, but 
      structure-function insight of HCCS is limited. Uniquely, euglenozoan protists, 
      which include medically relevant kinetoplastids Trypanosoma and Leishmania 
      parasites, attach heme to mitochondrial c-type cytochromes by a single thioether 
      linkage. Yet the mechanism is unknown, as genes encoding proteins with detectable 
      similarity to any proteins involved in cytochrome c maturation in other taxa are 
      absent. Here, a bioinformatics search for proteins conserved in all 
      hemoprotein-containing kinetoplastids identified kinetoplastid cytochrome c 
      synthetase (KCCS), which we reveal as essential and mitochondrial and catalyzes 
      heme attachment to trypanosome cytochrome c KCCS has no sequence identity to 
      other proteins, apart from a slight resemblance within four short motifs 
      suggesting relatedness to HCCS. Thus, KCCS provides a novel resource for studying 
      eukaryotic cytochrome c maturation, possibly with wider relevance, since 
      mutations in human HCCS leads to disease. Moreover, many examples of 
      mitochondrial biochemistry are different in euglenozoans compared to many other 
      eukaryotes; identification of KCCS thus provides another exemplar of extreme, 
      unusual mitochondrial biochemistry in an evolutionarily divergent group of 
      protists.IMPORTANCE Cytochromes c are essential proteins for respiratory and 
      photosynthetic electron transfer. They are posttranslationally modified by 
      covalent attachment of a heme cofactor. Kinetoplastids include important tropical 
      disease-causing parasites; many aspects of their biology differ from other 
      organisms, including their mammalian or plant hosts. Uniquely, kinetoplastids 
      produce cytochromes c with a type of heme attachment not seen elsewhere in nature 
      and were the only cytochrome c-bearing taxa without evidence of protein machinery 
      to attach heme to the apocytochrome. Using bioinformatics, biochemistry, and 
      molecular genetics, we report how kinetoplastids make their cytochromes c 
      Unexpectedly, they use a highly diverged version of an enzyme used for 
      heme-protein attachment in many eukaryotes. Mutations in the human enzyme lead to 
      genetic disease. Identification of kinetoplastid cytochrome c synthetase, thus, 
      solves an evolutionary unknown, provides a possible target for antiparasite drug 
      development, and an unanticipated resource for studying the mechanistic basis of 
      a human genetic disease.
CI  - Copyright (c) 2021 Belbelazi et al.
FAU - Belbelazi, Asma
AU  - Belbelazi A
AD  - School of Applied Sciences, University of Huddersfield, Huddersfield, United 
      Kingdom.
FAU - Neish, Rachel
AU  - Neish R
AD  - York Biomedical Research Institute, University of York, York, United Kingdom.
AD  - Department of Biology, University of York, York, United Kingdom.
FAU - Carr, Martin
AU  - Carr M
AD  - School of Applied Sciences, University of Huddersfield, Huddersfield, United 
      Kingdom.
FAU - Mottram, Jeremy C
AU  - Mottram JC
AUID- ORCID: 0000-0001-5574-3766
AD  - York Biomedical Research Institute, University of York, York, United Kingdom 
      jeremy.mottram@york.ac.uk m.ginger@hud.ac.uk.
AD  - Department of Biology, University of York, York, United Kingdom.
FAU - Ginger, Michael L
AU  - Ginger ML
AUID- ORCID: 0000-0002-9643-8482
AD  - School of Applied Sciences, University of Huddersfield, Huddersfield, United 
      Kingdom jeremy.mottram@york.ac.uk m.ginger@hud.ac.uk.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - 200807/Z/16/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210504
PL  - United States
TA  - mBio
JT  - mBio
JID - 101519231
RN  - 9007-43-6 (Cytochromes c)
RN  - EC 4.- (Lyases)
RN  - EC 4.4.1.17 (cytochrome C synthetase)
SB  - IM
MH  - Computational Biology
MH  - Cytochromes c/*genetics/*physiology
MH  - Eukaryota/*physiology
MH  - Leishmania mexicana/genetics/physiology
MH  - Lyases/chemistry/genetics/metabolism
MH  - Trypanosoma brucei brucei/genetics/physiology
PMC - PMC8262978
OTO - NOTNLM
OT  - Leishmania
OT  - Trypanosoma brucei
OT  - cytochrome c
OT  - mitochondrial metabolism
OT  - posttranslational modification
OT  - posttranslational modification (PTM)
OT  - protist
OT  - protists
EDAT- 2021/05/06 06:00
MHDA- 2021/10/14 06:00
PMCR- 2021/05/04
CRDT- 2021/05/05 05:53
PHST- 2021/05/05 05:53 [entrez]
PHST- 2021/05/06 06:00 [pubmed]
PHST- 2021/10/14 06:00 [medline]
PHST- 2021/05/04 00:00 [pmc-release]
AID - mBio.00166-21 [pii]
AID - mBio00166-21 [pii]
AID - 10.1128/mBio.00166-21 [doi]
PST - epublish
SO  - mBio. 2021 May 4;12(3):e00166-21. doi: 10.1128/mBio.00166-21.