Isocitrate dehydrogenase is an enzyme converting isocitrate to α-ketoglutarate in the canonical tricarboxylic acid (TCA) cycle. There are three different types of isocitrate dehydrogenase documented in eukaryotes. Our study points out the complex evolutionary history of isocitrate dehydrogenases across kinetoplastids, where the common ancestor of Trypanosomatidae and Bodonidae was equipped with two isoforms of the isocitrate dehydrogenase enzyme: the NADP+-dependent isocitrate dehydrogenase 1 with possibly dual localization in the cytosol and mitochondrion and NADP+-dependent mitochondrial isocitrate dehydrogenase 2. In the extant trypanosomatids, isocitrate dehydrogenase 1 is present only in a few species suggesting that it was lost upon separation of Trypanosoma spp. and replaced by the mainly NADP+-dependent cytosolic isocitrate dehydrogenase 3 of bacterial origin in all the derived lineages. In this study, we experimentally demonstrate that the omnipresent isocitrate dehydrogenase 2 has a dual localization in both mitochondrion and cytosol in at least four species that possess only this isoform. The apparent lack of the NAD+-dependent isocitrate dehydrogenase activity in trypanosomatid mitochondrion provides further support to the existence of the noncanonical TCA cycle across trypanosomatids and the bidirectional activity of isocitrate dehydrogenase 3 when operating with NADP+ cofactor instead of NAD+. This observation can be extended to all 17 species analyzed in this study, except for Leishmania mexicana, which showed only low isocitrate dehydrogenase activity in the cytosol. The variability in isocitrate oxidation capacity among species may reflect the distinct metabolic strategies and needs for reduced cofactors in particular environments.

Department of Biochemistry Faculty of Natural Sciences Comenius University Bratislava Slovakia

Department of Parasitology Faculty of Science Charles University BIOCEV Vestec Czechia

Division of Infectious Diseases Department of Medicine Faculty of Medicine and Dentistry University of Alberta Edmonton Canada

Institute of Parasitology Biology Centre Czech Academy of Sciences České Budějovice Czechia

Life Science Research Centre Faculty of Science University of Ostrava Ostrava Czechia

Zobrazit více v PubMed

Albanaz  ATS, Carrington  M, Frolov  AO, Ganyukova  AI, Gerasimov  ES, Kostygov  AY, Lukeš  J, Malysheva  MN, Votýpka  J, Zakharova  A, et al.  Shining the spotlight on the neglected: new high-quality genome assemblies as a gateway to understanding the evolution of Trypanosomatidae. BMC Genomics. 2023:24(1):471. 10.1186/s12864-023-09591-z. PubMed DOI PMC

Andrade-Alviárez  D, Bonive-Boscan  AD, Cáceres  AJ, Quiñones  W, Gualdrón-López  M, Ginger  ML, Michels  PAM. Delineating transitions during the evolution of specialised peroxisomes: glycosome formation in kinetoplastid and diplonemid protists. Front Cell Dev Biol. 2022:10:979269. 10.3389/fcell.2022.979269. PubMed DOI PMC

Armenteros  JJA, Salvatore  M, Emanuelsson  O, Winther  O, von Heijne  G, Elofsson  A, Nielsen  H. Detecting sequence signals in targeting peptides using deep learning. Life Sci Alliance. 2019:2(5):e201900429. 10.26508/lsa.201900429. PubMed DOI PMC

Besteiro  S, Barrett  MP, Rivière  L, Bringaud  F. Energy generation in insect stages of Trypanosoma brucei: metabolism in flux. Trends Parasitol. 2005:21(4):185–191. 10.1016/j.pt.2005.02.008. PubMed DOI

Bringaud  F, Rivière  L, Coustou  V. Energy metabolism of trypanosomatids: adaptation to available carbon sources. Mol Biochem Parasitol. 2006:149(1):1–9. 10.1016/j.molbiopara.2006.03.017. PubMed DOI

Camacho  C, Coulouris  G, Avagyan  V, Ma  N, Papadopoulos  J, Bealer  K, Madden  TL. BLAST+: architecture and applications. BMC Bioinformatics. 2009:10(1):421. 10.1186/1471-2105-10-421. PubMed DOI PMC

Capella-Gutiérrez  S, Silla-Martinez  JM, Gabaldon  T. TrimAl: a tool for automated alignment trimming in large-scale phylogenetic analyses. Bioinformatics. 2009:25(15):1972–1973. 10.1093/bioinformatics/btp348. PubMed DOI PMC

Carver  T, Harris  SR, Berriman  M, Parkhill  J, McQuillan  JA. Artemis: an integrated platform for visualization and analysis of high-throughput sequence-based experimental data. Bioinformatics. 2012:28(4):464–469. 10.1093/bioinformatics/btr703. PubMed DOI PMC

Castro  H, Romao  S, Carvalho  S, Teixeira  F, Sousa  C, Tomás  AM. Mitochondrial redox metabolism in trypanosomatids is independent of tryparedoxin activity. PLoS One. 2010:5(9):e12607. 10.1371/journal.pone.0012607. PubMed DOI PMC

Cavalcanti  JH, Esteves-Ferreira  AA, Quinhones  CG, Pereira-Lima  IA, Nunes-Nesi  A, Fernie  AR, Araújo  WL. Evolution and functional implications of the tricarboxylic acid cycle as revealed by phylogenetic analysis. Genome Biol Evol. 2014:6(10):2830–2848. 10.1093/gbe/evu221. PubMed DOI PMC

Chen  X, Sun  P, Liu  Y, Shen  S, Ma  T, Ding  J. Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction. J Biol Chem. 2022:298(12):102695. 10.1016/j.jbc.2022.102695. PubMed DOI PMC

Colasante  C, Ellis  M, Ruppert  T, Voncken  F. Comparative proteomics of glycosomes from bloodstream form and procyclic culture form Trypanosoma brucei brucei. Proteomics. 2006:6(11):3275–3293. 10.1002/pmic.200500668. PubMed DOI

Corpas  FJ, Barroso  JB, Sandalio  LM, Palma  JM, Lupiáñez  JA, del Río  LA. Peroxisomal NADP-dependent isocitrate dehydrogenase. Characterization and activity regulation during natural senescence. Plant Physiol. 1999:121(3):921–928. 10.1104/pp.121.3.921. PubMed DOI PMC

Coustou  V, Besteiro  S, Biran  M, Diolez  P, Bouchaud  V, Voisin  P, Michels  PA, Canioni  P, Baltz  T, Bringaud  F. ATP generation in the Trypanosoma brucei procyclic form: cytosolic substrate level is essential, but not oxidative phosphorylation. J Biol Chem. 2003:278(49):49625–49635. 10.1074/jbc.M307872200. PubMed DOI

Dean  AM, Lee  MH, Koshland  DE  Jr. Phosphorylation inactivates Escherichia coli isocitrate dehydrogenase by preventing isocitrate binding. J Biol Chem. 1989:264(34):20482–20486. 10.1016/S0021-9258(19)47087-7. PubMed DOI

Durieux  PO, Schütz  P, Brun  R, Köhler  P. Alterations in Krebs cycle enzyme activities and carbohydrate catabolism in two strains of Trypanosoma brucei during in vitro differentiation of their bloodstream to procyclic stages. Mol Biochem Parasitol. 1991:45(1):19–27. 10.1016/0166-6851(91)90023-Y. PubMed DOI

Eddy  SR. Accelerated profile HMM searches. PLoS Comput Biol. 2011:7(10):e1002195. 10.1371/journal.pcbi.1002195. PubMed DOI PMC

Evans  J, Sullivan  J. Approximating model probabilities in Bayesian information criterion and decision-theoretic approaches to model selection in phylogenetics. Mol Biol Evol. 2011:28(1):343–349. 10.1093/molbev/msq195. PubMed DOI PMC

Fernández-Ramos  C, Luque  F, Fernández-Becerra  C, Osuna  A, Jankevicius  SI, Jankevicius  JV, Rosales  MJ, Sánchez-Moreno  M. Biochemical characterisation of flagellates isolated from fruits and seeds from Brazil. FEMS Microbiol Lett. 1999:170(2):343–348. 10.1111/j.1574-6968.1999.tb13393.x. DOI

Frolov  AO, Kostygov  AY, Yurchenko  V. Development of monoxenous trypanosomatids and phytomonads in insects. Trends Parasitol. 2021:37(6):538–551. 10.1016/j.pt.2021.02.004. PubMed DOI

Galland  N, Demeure  F, Hannaert  V, Verplaetse  E, Vertommen  D, Van der Smissen  P, Courtoy  PJ, Michels  PA. Characterization of the role of the receptors PEX5 and PEX7 in the import of proteins into glycosomes of Trypanosoma brucei. Biochim Biophys Acta. 2007:1773(4):521–535. 10.1016/j.bbamcr.2007.01.006. PubMed DOI

Giordana  L, Nowicki  C. Two phylogenetically divergent isocitrate dehydrogenases are encoded in Leishmania parasites. Molecular and functional characterization of Leishmania mexicana isoenzymes with specificity towards NAD+ and NADP+. Mol Biochem Parasitol. 2020:240:111320. 10.1016/j.molbiopara.2020.111320. PubMed DOI

Guindon  S, Dufayard  JF, Lefort  V, Anisimova  M, Hordijk  W, Gascuel  O. New algorithms and methods to estimate maximum-likelihood phylogenies: assessing the performance of PhyML 3.0. Syst Biol. 2010:59(3):307–321. 10.1093/sysbio/syq010. PubMed DOI

Hoang  DT, Chernomor  O, von Haeseler  A, Minh  BQ, Vinh  LS. UFBoot2: improving the ultrafast bootstrap approximation. Mol Biol Evol. 2018:35(2):518–522. 10.1093/molbev/msx281. PubMed DOI PMC

Hurley  JH, Chen  R, Dean  AM. Determinants of cofactor specificity in isocitrate dehydrogenase: structure of an engineered NADP+ -> NAD+ specificity-reversal mutant. Biochemistry. 1996:35(18):5670–5678. 10.1021/bi953001q. PubMed DOI

Jackson  AP, Otto  TD, Aslett  M, Armstrong  SD, Bringaud  F, Schlacht  A, Hartley  C, Sanders  M, Wastling  JM, Dacks  JB, et al.  Kinetoplastid phylogenomics reveals the evolutionary innovations associated with the origins of parasitism. Curr Biol. 2016:26(2):161–172. 10.1016/j.cub.2015.11.055. PubMed DOI PMC

Jo  SH, Son  MK, Koh  HJ, Lee  SM, Song  IH, Kim  YO, Lee  YS, Jeong  KS, Kim  WB, Park  JW, et al.  Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase. J Biol Chem. 2001:276(19):16168–16176. 10.1074/jbc.M010120200. PubMed DOI

Kalyaanamoorthy  S, Minh  BQ, Wong  TKF, von Haeseler  A, Jermiin  LS. ModelFinder: fast model selection for accurate phylogenetic estimates. Nat Methods. 2017:14(6):587–589. 10.1038/nmeth.4285. PubMed DOI PMC

Katoh  K, Standley  DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol. 2013:30(4):772–780. 10.1093/molbev/mst010. PubMed DOI PMC

Koh  HJ, Lee  SM, Son  BG, Lee  SH, Ryoo  ZY, Chang  KT, Park  JW, Park  DC, Song  BJ, Veech  RL, et al.  Cytosolic NADP+-dependent isocitrate dehydrogenase plays a key role in lipid metabolism. J Biol Chem. 2004:279(38):39968–39974. 10.1074/jbc.M402260200. PubMed DOI

Kostygov  AY, Albanaz  ATS, Butenko  A, Gerasimov  ES, Lukeš  J, Yurchenko  V. Phylogenetic framework to explore trait evolution in Trypanosomatidae. Trends Parasitol. 2024:40(2):96–99. 10.1016/j.pt.2023.11.009. PubMed DOI

Kostygov  AY, Karnkowska  A, Votýpka  J, Tashyreva  D, Maciszewski  K, Yurchenko  V, Lukeš  J. Euglenozoa: taxonomy, diversity and ecology, symbioses and viruses. Open Biol. 2021:11(3):200407. 10.1098/rsob.200407. PubMed DOI PMC

Kovářová  J, Barrett  MP. The pentose phosphate pathway in parasitic trypanosomatids. Trends Parasitol. 2016:32(8):622–634. 10.1016/j.pt.2016.04.010. PubMed DOI

Kraeva  N, Ishemgulova  A, Lukeš  J, Yurchenko  V. Tetracycline-inducible gene expression system in Leishmania mexicana. Mol Biochem Parasitol. 2014:198(1):11–13. 10.1016/j.molbiopara.2014.11.002. PubMed DOI

Kume  K, Amagasa  T, Hashimoto  T, Kitagawa  H. NommPred: prediction of mitochondrial and mitochondrion-related organelle proteins of nonmodel organisms. Evol Bioinform. 2018:14:1176934318819835. 10.1177/1176934318819835. PubMed DOI PMC

Lane  N. Transformer: the deep chemistry of life and death. New York (NY): W.W. Norton & Co; 2022.

Leroux  AE, Maugeri  DA, Cazzulo  JJ, Nowicki  C. Functional characterization of NADP-dependent isocitrate dehydrogenase isozymes from Trypanosoma cruzi. Mol Biochem Parasitol. 2011:177(1):61–64. 10.1016/j.molbiopara.2011.01.010. PubMed DOI

Lewis  CA, Parker  SJ, Fiske  BP, McCloskey  D, Gui  DY, Green  CR, Vokes  NI, Feist  AM, Vander Heiden  MG, Metallo  CM. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014:55(2):253–263. 10.1016/j.molcel.2014.05.008. PubMed DOI PMC

Lin  AP, McAlister-Henn  L. Homologous binding sites in yeast isocitrate dehydrogenase for cofactor (NAD+) and allosteric activator (AMP). J Biol Chem. 2003:278(15):12864–12872. 10.1074/jbc.M300154200. PubMed DOI

Louassini  M, Foulquie  M, Benitez  R, Adroher  J. Citric-acid cycle key enzyme activities during in vitro growth and metacyclogenesis of Leishmania infantum promastigotes. J Parasitol. 1999:85(4):595–602. 10.2307/3285729. PubMed DOI

Lukeš  J, Skalický  T, Týč  J, Votýpka  J, Yurchenko  V. Evolution of parasitism in kinetoplastid flagellates. Mol Biochem Parasitol. 2014:195(2):115–122. 10.1016/j.molbiopara.2014.05.007. PubMed DOI

Meade  JC, Glaser  TA, Bonventre  PF, Mukkada  AJ. Enzymes of carbohydrate metabolism in Leishmania donovani amastigotes. J Protozool. 1984:31(1):156–161. 10.1111/j.1550-7408.1984.tb04307.x. PubMed DOI

Michels  PAM, Villafraz  O, Pineda  E, Alencar  MB, Cáceres  AJ, Silber  AM, Bringaud  F. Carbohydrate metabolism in trypanosomatids: new insights revealing novel complexity, diversity and species-unique features. Exp Parasitol. 2021:224:108102. 10.1016/j.exppara.2021.108102. PubMed DOI

Mistry  J, Chuguransky  S, Williams  L, Qureshi  M, Salazar  GA, Sonnhammer  ELL, Tosatto  SCE, Paladin  L, Raj  S, Richardson  LJ, et al.  Pfam: the protein families database in 2021. Nucleic Acids Res. 2021:49(D1):D412–D419. 10.1093/nar/gkaa913. PubMed DOI PMC

Nguyen  LT, Schmidt  HA, von Haeseler  A, Minh  BQ. IQ-TREE: a fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies. Mol Biol Evol. 2015:32(1):268–274. 10.1093/molbev/msu300. PubMed DOI PMC

Opperdoes  FR, Butenko  A, Flegontov  P, Yurchenko  V, Lukeš  J. Comparative metabolism of free-living Bodo saltans and parasitic trypanosomatids. J Eukaryot Microbiol. 2016:63(5):657–678. 10.1111/jeu.12315. PubMed DOI

Opperdoes  FR, Butenko  A, Zakharova  A, Gerasimov  ES, Zimmer  SL, Lukeš  J, Yurchenko  V.  The remarkable metabolism of Vickermania ingenoplastis: genomic predictions. Pathogens. 2021:10(1):68. 10.3390/pathogens10010068. PubMed DOI PMC

Panigrahi  AK, Zíková  A, Dalley  RA, Acestor  N, Ogata  Y, Anupama  A, Myler  PJ, Stuart  KD. Mitochondrial complexes in Trypanosoma brucei: a novel complex and a unique oxidoreductase complex. Mol Cell Proteomics. 2008:7(3):534–545. 10.1074/mcp.M700430-MCP200. PubMed DOI

Porcel  BM, Denoeud  F, Opperdoes  F, Noel  B, Madoui  MA, Hammarton  TC, Field  MC, Da Silva  C, Couloux  A, Poulain  J, et al.  The streamlined genome of Phytomonas spp. relative to human pathogenic kinetoplastids reveals a parasite tailored for plants. PLoS Genet. 2014:10(2):e1004007. 10.1371/journal.pgen.1004007. PubMed DOI PMC

Pyrih  J, Hammond  M, Alves  A, Dean  S, Sunter  JD, Wheeler  RJ, Gull  K, Lukeš  J.  Comprehensive sub-mitochondrial protein map of the parasitic protist Trypanosoma brucei defines critical features of organellar biology. Cell Rep. 2023:42(9):113083. 10.1016/j.celrep.2023.113083. PubMed DOI

Qi  F, Chen  X, Beard  DA. Detailed kinetics and regulation of mammalian NAD-linked isocitrate dehydrogenase. Biochim Biophys Acta. 2008:1784(11):1641–1651. 10.1016/j.bbapap.2008.07.001. PubMed DOI PMC

Ronquist  F, Teslenko  M, van der Mark  P, Ayres  DL, Darling  A, Höhna  S, Larget  B, Liu  L, Suchard  MA, Huelsenbeck  JP. Mrbayes 3.2: efficient Bayesian phylogenetic inference and model choice across a large model space. Syst Biol. 2012:61(3):539–542. 10.1093/sysbio/sys029. PubMed DOI PMC

Saunders  EC, Ng  WW, Chambers  JM, Ng  M, Naderer  T, Krömer  JO, Likic  VA, McConville  MJ. Isotopomer profiling of Leishmania mexicana promastigotes reveals important roles for succinate fermentation and aspartate uptake in tricarboxylic acid cycle (TCA) anaplerosis, glutamate synthesis, and growth. J Biol Chem. 2011:286(31):27706–27717. 10.1074/jbc.M110.213553. PubMed DOI PMC

Saunders  EC, Ng  WW, Kloehn  J, Chambers  JM, Ng  M, McConville  MJ. Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism. PLoS Pathog. 2014:10(1):e1003888. 10.1371/journal.ppat.1003888. PubMed DOI PMC

Schenk  R, Bachmaier  S, Bringaud  F, Boshart  M. Efficient flavinylation of glycosomal fumarate reductase by its own ApbE domain in Trypanosoma brucei. FEBS J. 2021:288(18):5430–5445. 10.1111/febs.15812. PubMed DOI

Skalický  T, Dobáková  E, Wheeler  RJ, Tesařová  M, Flegontov  P, Jirsová  D, Votýpka  J, Yurchenko  V, Ayala  FJ, Lukeš  J. Extensive flagellar remodeling during the complex life cycle of Paratrypanosoma, an early-branching trypanosomatid. Proc Natl Acad Sci U S A. 2017:114(44):11757–11762. 10.1073/pnas.1712311114. PubMed DOI PMC

Škodová-Sveráková  I, Verner  Z, Skalický  T, Votýpka  J, Horváth  A, Lukeš  J. Lineage-specific activities of a multipotent mitochondrion of trypanosomatid flagellates. Mol Microbiol. 2015:96(1):55–67. 10.1111/mmi.12920. PubMed DOI

Spaans  SK, Weusthuis  RA, van der Oost  J, Kengen  SW. NADPH-generating systems in bacteria and archaea. Front Microbiol. 2015:6:742. 10.3389/fmicb.2015.00742. PubMed DOI PMC

Steinegger  M, Söding  J. MMseqs2 enables sensitive protein sequence searching for the analysis of massive data sets. Nat Biotechnol. 2017:35(11):1026–1028. 10.1038/nbt.3988. PubMed DOI

Stuart  K, Brun  R, Croft  S, Fairlamb  A, Gürtler  RE, McKerrow  J, Reed  S, Tarleton  R. Kinetoplastids: related protozoan pathogens, different diseases. J Clin Invest. 2008:118(4):1301–1310. 10.1172/JCI33945. PubMed DOI PMC

Thumuluri  V, Armenteros  JJA, Johansen  AR, Nielsen  H, Winther  O. DeepLoc 2.0: multi-label subcellular localization prediction using protein language models. Nucleic Acids Res. 2022:50(W1):W228–W234. 10.1093/nar/gkac278. PubMed DOI PMC

van Hellemond  JJ, Opperdoes  FR, Tielens  AG. The extraordinary mitochondrion and unusual citric acid cycle in Trypanosoma brucei. Biochem Soc Trans. 2005:33(5):967–971. 10.1042/BST0330967. PubMed DOI

van Weelden  SW, Fast  B, Vogt  A, van der Meer  P, Saas  J, van Hellemond  JJ, Tielens  AG, Boshart  M. Procyclic Trypanosoma brucei do not use Krebs cycle activity for energy generation. J Biol Chem. 2003:278(15):12854–12863. 10.1074/jbc.M213190200. PubMed DOI

van Weelden  SW, van Hellemond  JJ, Opperdoes  FR, Tielens  AG. New functions for parts of the Krebs cycle in procyclic Trypanosoma brucei, a cycle not operating as a cycle. J Biol Chem. 2005:280(13):12451–12460. 10.1074/jbc.M412447200. PubMed DOI

Verner  Z, Cermáková  P, Skodová  I, Kováčová  B, Lukeš  J, Horváth  A. Comparative analysis of respiratory chain and oxidative phosphorylation in Leishmania tarentolae, Crithidia fasciculata, Phytomonas serpens and procyclic stage of Trypanosoma brucei. Mol Biochem Parasitol. 2014:193(1):55–65. 10.1016/j.molbiopara.2014.02.003. PubMed DOI

Villafraz  O, Biran  M, Pineda  E, Plazolles  N, Cahoreau  E, Ornitz Oliveira Souza  R, Thonnus  M, Allmann  S, Tetaud  E, Rivière  L, et al.  Procyclic trypanosomes recycle glucose catabolites and TCA cycle intermediates to stimulate growth in the presence of physiological amounts of proline. PLoS Pathog. 2021:17(3):e1009204. 10.1371/journal.ppat.1009204. PubMed DOI PMC

Vinekar  R, Verma  C, Ghosh  I. Functional relevance of dynamic properties of dimeric NADP-dependent isocitrate dehydrogenases. BMC Bioinformatics. 2012:13(S17):S2. 10.1186/1471-2105-13-S17-S2. PubMed DOI PMC

Wang  X, Inaoka  DK, Shiba  T, Balogun  EO, Allmann  S, Watanabe  YI, Boshart  M, Kita  K, Harada  S. Expression, purification, and crystallization of type 1 isocitrate dehydrogenase from Trypanosoma brucei brucei. Protein Expr Purif. 2017:138:56–62. 10.1016/j.pep.2017.06.011. PubMed DOI

Wang  P, Lv  C, Zhu  G. Novel type II and monomeric NAD+ specific isocitrate dehydrogenases: phylogenetic affinity, enzymatic characterization, and evolutionary implication. Sci Rep. 2015:5(1):9150. 10.1038/srep09150. PubMed DOI PMC

Wang  HC, Minh  BQ, Susko  E, Roger  AJ. Modeling site heterogeneity with posterior mean site frequency profiles accelerates accurate phylogenomic estimation. Syst Biol. 2018:67(2):216–235. 10.1093/sysbio/syx068. PubMed DOI

Wargnies  M, Plazolles  N, Schenk  R, Villafraz  O, Dupuy  JW, Biran  M, Bachmaier  S, Baudouin  H, Clayton  C, Boshart  M, et al.  Metabolic selection of a homologous recombination-mediated gene loss protects Trypanosoma brucei from ROS production by glycosomal fumarate reductase. J Biol Chem. 2021:296:100548. 10.1016/j.jbc.2021.100548. PubMed DOI PMC

Xiao  W, Wang  RS, Handy  DE, Loscalzo  J. 2018. NAD(H) and NADP(H) redox couples and cellular energy metabolism. Antioxid Redox Signal. 28(3):251–272. 10.1089/ars.2017.7216. PubMed DOI PMC

Xu  X, Zhao  J, Xu  Z, Peng  B, Huang  Q, Arnold  E, Ding  J. Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. J Biol Chem. 2004:279(32):33946–33957. 10.1074/jbc.M404298200. PubMed DOI

Yurchenko  V, Kostygov  A, Havlová  J, Grybchuk-Ieremenko  A, Ševčíková  T, Lukeš  J, Ševčík  J, Votýpka  J. Diversity of trypanosomatids in cockroaches and the description of Herpetomonas tarakana sp. n. J Eukaryot Microbiol. 2016:63(2):198–209. 10.1111/jeu.12268. PubMed DOI