Figure 1.
Biosynthesis of riboflavin and FAD.
Metabolites - I: Guanosine 5'-triphosphate; II: 2,5-Diamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one; III: 5-Amino-6-(5'-phosphoribosylamino)uracil; IV: 5-Amino-6-(5'-phospho-D-ribitylamino)uracil; V: 5-Amino-6-(1-D-ribitylamino)uracil; VI: D-Ribulose 5-phosphate; VII: 2-Hydroxy-3-oxobutyl phosphate; VIII: 6,7-Dimethyl-8-(D-ribityl)lumazine; IX: Riboflavin; X: Flavin mononucleotide; XI: Flavin adenine dinucleotide Enzymes - 3.5.4.25: GTP cyclohydrolase II; 3.5.4.26: diaminohydroxyphosphoribosylaminopyrimidine deaminase; 1.1.1.193: 5-amino-6-(5-phosphoribosylamino)uracil reductase; 3.1.3.-: Phosphoric monoester hydrolases; 4.1.99.12: 3,4-dihydroxy 2-butanone 4-phosphate synthase; 2.5.1.78: 6,7-dimethyl-8-ribityllumazine synthase; 2.5.1.9: riboflavin synthase; 2.7.1.26: riboflavin kinase; 2.7.7.2: FAD synthetase.
Figure 2.
Biosynthesis of pantothenic acid and coenzyme A.
Enzymes surrounded by a gray box were possibly acquired through horizontal transfer from Bacteria to trypanosomatids (see main text). Metabolites - I: Aspartate; II: β-Alanine; III: α-ketoisovalerate; IV: 2-Dehydropantoate; V: Pantoate; VI: Pantothenic acid; VII: D-4'-Phosphopantothenate; VIII: (R)-4'-Phosphopantothenoyl-L-cysteine; IX: Pantetheine 4'-phosphate; X: Dephosphocoenzyme A; XI: Coenzyme A. Enzymes - 4.1.1.11: aspartate 1-decarboxylase; 2.1.2.11: 3-methyl-2-oxobutanoate hydroxymethyltransferase; 1.1.1.169: ketopantoate reductase; 6.3.2.1: pantoate--beta-alanine ligase; 2.7.1.33: pantothenate kinase; 6.3.2.5: phosphopantothenate-cysteine ligase; 4.1.1.36: phosphopantothenoylcysteine decarboxylase; 2.7.7.3: pantetheine-phosphate adenylyltransferase; 2.7.1.24: dephospho-CoA kinase.
Figure 3.
Metabolites - I: D-Erythrose 4-phosphate; II: 4-Phospho-D-erythronate; III: 2-Oxo-3-hydroxy-4-phosphobutanoate; IV: 4-phospho-hydroxy-L-threonine; V: 2-amino-3-oxo-4-phosphonooxybutyrate; VI: 3-Amino-2-oxopropyl phosphate; VII: D-glyceraldehyde 3-phosphate; VIII: pyruvate; IX: 1-deoxy-D-xylulose 5-phosphate; X: Pyridoxine phosphate; XI: Pyridoxal 5’-phosphate (PLP); XII: Pyridoxamine phosphate; XIII: Pyridoxine; XIV: Pyridoxal; XV: Pyridoxamine. Enzymes - 1.2.1.72: D-erythrose 4-phosphate dehydrogenase; 1.1.1.290: erythronate-4-phosphate dehydrogenase; 2.6.1.52: phosphoserine aminotransferase; 1.1.1.262: 4-hydroxythreonine-4-phosphate dehydrogenase; 2.2.1.7: 1-deoxyxylulose-5-phosphate synthase; 2.6.99.2: pyridoxine 5-phosphate synthase; 1.4.3.5: pyridoxamine 5'-phosphate oxidase; 2.7.1.35: pyridoxal kinase.
Figure 4.
Metabolites - I: Guanosine 5'-triphosphate; II: 7,8-Dihydroneopterin 3'-triphosphate; III: Dihydroneopterin; IV: 2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine; V: 2-Amino-7,8-dihydro-4-hydroxy-6-(diphosphooxymethyl)pteridine; VI: para-aminobenzoate; VII: Dihydropteroate; VIII: L-glutamate; IX: Dihydrofolate; X: Tetrahydrofolate; XI: Folic acid. Enzymes - 3.5.4.16: GTP cyclohydrolase I; 3.1.3.1: alkaline phosphatase; 3.6.1.-: Hydrolase acting on acid anhydrides in phosphorus-containing anhydrides; 4.2.1.25: dihydroneopterin aldolase; 2.7.6.3: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase; 2.5.1.15: dihydropteroate synthase; 6.3.2.12: dihydrofolate synthase; 6.3.2.17: folylpolyglutamate synthase; 1.5.1.3: dihydrofolate reductase.
Figure 5.
Metabolites - I: L-Cysteine; II: a [ThiI sulfur-carrier protein]-L-cysteine; III: a [ThiI sulfur-carrier protein]-S-sulfanylcysteine; IV: a ThiS sulfur carrier protein; V: a carboxy-adenylated-[ThiS sulfur-carrier protein]; VI: Thiamine biosynthesis intermediate 5; VII: a thiocarboxy-adenylated-[ThiS-protein]; VIII: L-Tyrosine; IX: Glycine; X: Iminoglycine; XI: 4-Methyl-5-(2-phosphoethyl)-thiazole; XII: 5'-Phosphoribosyl-5-aminoimidazole; XIII: 4-Amino-5-hydroxymethyl-2-methylpyrimidine; XIV: 4-Amino-2-methyl-5-phosphomethylpyrimidine; XV: 2-Methyl-4-amino-5-hydroxymethylpyrimidine diphosphate; XVI: Thiamine monophosphate; XVII: Thiamine diphosphate. Enzymes - 2.8.1.7: cysteine desulfurase; 2.7.7.73: sulfur carrier protein ThiS adenylyltransferase; 2.8.1.4: thiamine biosynthesis protein ThiI; 1.4.3.19: glycine oxidase; 2.8.1.10: thiamine biosynthesis ThiG; 4.1.99.19: thiamine biosynthesis ThiH; 4.1.99.17: thiamine biosynthesis protein ThiC; 2.7.1.49: hydroxymethylpyrimidine kinase; 2.7.4.7: phosphomethylpyrimidine kinase; 2.5.1.3: thiamine-phosphate pyrophosphorylase; 2.7.4.16: thiamine-monophosphate kinase.
Figure 6.
Biosynthesis of nicotinic acid and NAD.
Enzymes surrounded by a gray box were possibly acquired through horizontal transfer from Bacteria to trypanosomatids (see main text). Metabolites - I: Aspartate; II: Glycerone-phosphate; III: Iminoaspartate; IV: Quinolinate; V: Nicotinate D-ribonucleotide; VI: Deamino-NAD+; VII: Nicotinamide adenine dinucleotide; VIII: Nicotinamide adenine dinucleotide phosphate; IX: Tryptophan; X: L-Formylkynurenine; XI: L-Kynurenine; XII: 3-Hydroxy-L-kynurenine; XIII: 3-Hydroxyanthranilate; XIV: 2-Amino-3-carboxymuconate semialdehyde; XV: Nicotinic acid; XVI: Nicotinamide. Enzymes - 1.4.3.16: L-aspartate oxidase; 1.4.1.21: aspartate dehydrogenase; 2.5.1.72: quinolinate synthase; 2.4.2.19: nicotinate-nucleotide diphosphorylase; 2.7.7.18:; 6.3.5.1: NAD+ synthase; 2.7.1.23: NAD+ kinase; 1.13.11.11: tryptophan 2,3-dioxygenase; 3.5.1.9: arylformamidase; 1.14.13.9: kynurenine 3-monooxygenase; 3.7.1.3 kynureninase; 1.13.11.6: 3-hydroxyanthranilate 3,4-dioxygenase; 2.4.2.11: nicotinate phosphoribosyltransferase (recently transferred to EC6.3.4.21); 3.5.1.19: nicotinamidase.
Figure 7.
Metabolites - I: malonyl-CoA; II: malonyl-CoA methyl ester; III: a 3-oxo-glutaryl-[acp] methyl ester; IV: a 3-hydroxyglutaryl-[acp] methyl ester; V: an enoylglutaryl-[acp] methyl ester; VI: a glutaryl-[acp] methyl ester; VII: a 3-oxo-pimelyl-[acp] methyl ester; VIII: a 3-hydroxypimelyl-[acp] methyl ester; IX: an enoylpimelyl-[acp] methyl ester; X: a pimelyl-[acp] methyl ester; XI: a pimelyl-[acp]; XII: 7-keto-8-aminopelargonate; XIII: 7,8-diaminopelargonate; XIV: dethiobiotin; XV: biotin. Enzymes - 2.1.1.197: malonyl-CoA methyltransferase; 2.3.1.180: β-ketoacyl-acyl carrier protein synthase III; 1.1.1.100: 3-oxo-acyl-[acyl-carrier-protein] reductase; 2.4.1.59: 3-hydroxy-acyl-[acyl-carrier-protein] dehydratase; 1.3.1.10: enoyl-[acyl-carrier-protein] reductase; 2.3.1.41: β-ketoacyl-ACP synthase I; 3.1.1.85: pimeloyl-[acp] methyl ester esterase; 2.3.1.47: 8-amino-7-oxononanoate synthase; 2.6.1.62: 7,8-diaminopelargonic acid synthase; 6.3.3.3: dethiobiotin synthetase; 2.8.1.6: biotin synthase.
Figure 8.
Enzymes surrounded by a gray box were possibly acquired through horizontal transfer from Bacteria to trypanosomatids (see main text). Metabolites - I: L-Tyrosine; II: 4-Hydroxyphenylpyruvate; III: 4-Hydroxyphenyllactate; IV: 4-Coumarate; V: 4-Coumaroyl-CoA; VI: 4-Hydroxybenzoyl-CoA; VII: 4-Hydroxybenzoate; VIII: Chorismate; IX: 4-Hydroxy-3-polyprenylbenzoate; X: 2-Polyprenylphenol; XI: 2-Polyprenyl-6-hydroxyphenol; XII: 2-Polyprenyl-6-methoxyphenol; XIII: 2-Polyprenyl-6-methoxy-1,4-benzoquinone; XIV: 2-Polyprenyl-3-methyl-6-methoxy-1,4-benzoquinone; XV: 2-Polyprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone; XVI: Ubiquinone. Enzymes - 2.6.1.5: tyrosine aminotransferase; 1.1.1.237: hydroxyphenylpyruvate reductase; 6.2.1.12: 4-coumarate--CoA ligase; 3.1.2.23: 4-hydroxybenzoyl-CoA thioesterase; UbiC: chorismate lyase; UbiA/Coq2: 4-hydroxybenzoate polyprenyltransferase; UbiD/UbiX: 3-octaprenyl-4-hydroxybenzoate carboxy-lyase; UbiB: ubiquinone biosynthesis protein; UbiG (EC:2.1.1.222): 2-polyprenyl-6-hydroxyphenyl methylase; UbiH/Coq6: 2-octaprenyl-6-methoxyphenol hydroxylase; UbiE/Coq5: ubiquinone biosynthesis methyltransferase; UbiF/Coq7: 2-octaprenyl-3-methyl-6-methoxy-1,4-benzoquinol hydroxylase; UbiG/Coq3 (EC:2.1.1.64/EC:2.1.1.114): 3-demethylubiquinol 3-O-methyltransferase/hexaprenyldihydroxybenzoate methyltransferase.
Figure 9.
Maximum likelihood phylogenetic tree of ketopantoate reductase (EC:1.1.1.169).
A -overall tree, colored according to taxonomic affiliation of each taxon, as per the legend on the left; distance bar only applies to panel A. B – details of the region of the tree where the Trypanosomatidae are placed. Values on nodes represent bootstrap support (only 50 or greater shown). Panel B is meant to only represent the branching patterns and do not portray estimated distances between sequences.
Figure 10.
Maximum likelihood phylogenetic tree of nicotinate phosphoribosyltransferase (EC:2.4.2.11).
A –overall tree, colored according to taxonomic affiliation of each taxon, as per the legend on the left; distance bar only applies to panel A. B – details of the region of the tree where the Ca. Kinetoplastibacterium spp. are placed. C – details of the region of the tree where the Trypanosomatidae are placed. Values on nodes represent bootstrap support (only 50 or greater shown). Panels B and C are meant to only represent the branching patterns and do not portray estimated distances between sequences.
Figure 11.
Maximum likelihood phylogenetic tree of UbiC (EC:4.1.3.40).
A –overall tree, colored according to taxonomic affiliation of each taxon, as per the legend on the left; distance bar only applies to panel A. B – details of the region of the tree where the Trypanosomatidae are placed. Values on nodes represent bootstrap support (only 50 or greater shown). Panel B is meant to only represent the branching patterns and do not portray estimated distances between sequences.
Figure 12.
Overview of the biosynthetic pathways of essential vitamins and cofactors in trypanosomatids.
Dashed arrows: metabolite import/exchange; dotted arrows: reaction present in only some of the organisms analyzed; solid arrows: other reactions (circles on the top of the arrows indicate number of steps and fulfilled circles indicate presence of enzyme); arrows surrounded by a gray box: enzymes possibly acquired through horizontal transfer from Bacteria to trypanosomatids (see main text). A - Contribution of SHTs and TPEs based on the analysis of gene content in the genomes of A. deanei, A. desouzai, S. culicis, S. oncopelti, S. galati and respective endosymbionts. B - Biochemical capability of trypanosomatids without symbionts based on the analysis of genomic data of H. muscarum, C. acanthocephali and L. major.