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THE EMBDEN–MEYERHOF–PARNAS (EMP) PATHWAY OF GLYCOLYSIS 141 eukaryotic cells. Whereas in most cells the glycolytic pathway takes place in the cytosol, in the trypanosome its first seven enzymes are localized within a membrane-bound organelle. In addition, two enzymes of glycerol metabolism and several enzymes of the hexosemonophosphate pathway are present in these organelles as well. Although this organelle resembles the peroxisomes found in other cell types, it lacks typical peroxisomal enzymes such as peroxidase, catalase and acylCoA oxidase. By contrast 90% of its protein represents glycolytic enzyme. Therefore, these highly specialized peroxisomes have been called ‘glycosomes’. Because neither a functional tricarboxylic acid cycle, nor a classical respiratory chain, are present in the organism’s single mitochondrion, the end-product of this metabolism is pyruvate, which is excreted directly into the host’s bloodstream rather than being metabolized to lactate or carbon dioxide plus water. Hence, little ATP is produced and that only by substrate-level phosphorylation. This low ATP yield explains the high rate of glucose consumption (Figure 7.4). Bloodstream forms contain neither carbohydrate stores, such as glycogen or other polysaccharides, nor any energy reserves of any significance, such as creatine phosphate or polyphosphates. Thus inhibition of the glycolytic pathway or depletion of an energy substrate such as glucose immediately results in a rapid drop of cellular ATP levels, a total loss of motility and disappearance of trypanosomes from the bloodstream of the infected host. The NADH produced during glycolysis in the glyceraldehyde-phosphate dehydrogenase reaction is reoxidized indirectly by molecular oxygen via a glycerol-3-phosphate (G3P):dihydroxyacetone-phosphate (DHAP) shuttle comprising the glycosomal NAD-linked G3P dehydrogenase and a FAD-linked G3P dehydrogenase present in the mitochondrial inner membrane, which catalyses the reversed reaction. Reducing equivalents produced by this cycle are supposed to react with ubiquinone present in the mitochondrial membrane. The ubiquinol thus formed is oxidized by a ubiquinol:oxygen oxidoreductase, also called trypanosome alternative oxidase (TAO), present in the mitochondrial inner membrane. This enzyme resembles the alternative oxidases of plants and certain fungi in that it is insensitive to cyanide, but is sensitive to salicyl hydroxamic acid (SHAM). Moreover, in a phylogenetic analysis its amino-acid sequence branched close to the alga C. reinhardtii and formed a single clade with the plant alternative oxidases with a high bootstrap support. This enzyme has also been detected in the plant trypanosomatid Phytomonas, but seems to be absent from Leishmania spp., where neither the activity nor the gene encoding the enzyme were detected. Inhibition of the TAO by SHAM mimics the effect of a lack of oxygen on carbohydrate metabolism of the bloodstream form. NAD is now regenerated by the reduction of DHAP to G3P, followed by the formation of glycerol which is excreted by the organism. The ATP synthesized in the latter reaction compensates for the loss of one mole of ATP in the glycosomal phosphoglycerate kinase reaction, because now one mole of phosphoglycerate, rather than two, is produced per mole of glucose consumed. As a consequence, glucose is dismutated into equimolar amounts of pyruvate and glycerol, with net synthesis of one molecule of ATP. Under these conditions bloodstream forms survive and remain motile, while cellular ATP levels drop to about 50%. Thus, inhibition of respiration alone is not sufficient to kill the organism and the trypanosomes survive for a prolonged time as long as glycerol does not accumulate in the medium. This probably explains why of the many new and effective inhibitors of the trypanosome alternative oxidase which have BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA
142 ENERGY METABOLISM – TRYPANOSOMATIDAE Glucose Cytosol 15 Glycosome Glucose ATP 1 ADP Glc-6-P AMP 2 10 Fru-6-P ATP ATP ADP 3 ADP Mitochondrion Fru-1,6-P 2 4 DHAP 5 H GAP 2 O SHAM NAD P 11 i ½ O 8 6 2 NADH AMP 10 ATP ADP glycerol-3-P glycerate-1,3-P 2 ATP ADP 9 ADP 7 ATP Glycerol 3-P-glycerate 2-P-glycerate 12 H 2 O Phosphoenolpyruvate ADP 13 ATP Pyruvate 16 17 Glycerol Pyruvate FIGURE 7.4 Glycolysis in the bloodstream-form trypanosome. Boxed metabolites are nutrients or end-products of metabolism. Enzymes: (1) hexokinase; (2) phosphoglucose isomerase; (3) phosphofructokinase; (4) aldolase; (5) triosephosphate isomerase; (6) glyceraldehyde-3-phosphate dehydrogenase; (7) phosphoglycerate kinase; (8) glycerol-3-phosphate dehydrogenase; (9) glycerol kinase; (10) adenylate kinase; (11) glycerol-3-phosphate oxidase; (12) phosphoglycerate mutase; (13) enolase; (14) pyruvate kinase; (15) glucose transporter; (16) glycerol transporter; (17) pyruvate transporter. BIOCHEMISTRY AND CELL BIOLOGY: PROTOZOA
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Molecular Medical Parasitology
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Molecular Medical Parasitology Edit
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Contents List of contributors Prefa
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List of contributors Mark Blaxter,
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LIST OF CONTRIBUTORS ix Richard. J.
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Preface Parasitology was born as th
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S E C T I O N I MOLECULAR BIOLOGY
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C H A P T E R 1 Parasite genomics M
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TABLE 1.1 Parasite genomes: genome
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GENERATING GENOMICS DATA 7 differen
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GENERATING GENOMICS DATA 9 TABLE 1.
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GENERATING GENOMICS DATA 11 called
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GENERATING GENOMICS DATA 13 200 000
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BIOINFORMATICS AND THE ANALYSIS OF
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THE POST-GENOMICS ERA, AND THE OTHE
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THE PARASITES AND THEIR GENOMES 19
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FURTHER READING 27 treated with a d
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C H A P T E R 2 RNA processing in p
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TRANS-SPLICING 31 cis trans Exon 1
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TRANS-SPLICING 33 snRNPs (small nuc
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TRANS-SPLICING 35 trans cis U2AF35
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RNA EDITING 37 P AAAA... AAAA... AA
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RNA EDITING 39 entire transcript re
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RNA EDITING 41 5 Editing block C Ed
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RNA EDITING 43 microscopy) approach
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FURTHER READING 45 Nilsen, T.W. (19
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C H A P T E R 3 Transcription Arthu
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UNUSUAL MODES OF TRANSCRIPTION IN T
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CLASS I TRANSCRIPTION IN TRYPANOSOM
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CLASS II TRANSCRIPTION OF PROTEIN C
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SL RNA AND U snRNA GENE TRANSCRIPTI
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FURTHER READING 65 and switching in
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C H A P T E R 4 Post-transcriptiona
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POST-TRANSCRIPTIONAL REGULATION IN
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FURTHER READING 87 inhibition, it m
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C H A P T E R 5 Antigenic variation
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Page 108 and 109: VSG Signal sequence Amino-terminal
Page 110 and 111: GENETICS OF ANTIGENIC VARIATION 97
Page 116 and 117: IMMUNE RESPONSES TO TRYPANOSOME INF
Page 118 and 119: INNATE RESISTANCE, HUMAN SUSCEPTIBI
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Page 122 and 123: FURTHER READING 109 ACKNOWLEDGEMENT
Page 124 and 125: C H A P T E R 6 Genetic and genomic
Page 126 and 127: ‘FORWARD’ VS. ‘REVERSE’ GEN
Page 128 and 129: EXAMPLES OF ‘FORWARD’ GENETIC A
Page 130 and 131: EXAMPLES OF ‘FORWARD’ GENETIC A
Page 132 and 133: REVERSE GENETICS AND LEISHMANIA VIR
Page 134 and 135: VALIDATION OF CANDIDATE VIRULENCE G
Page 136 and 137: S E C T I O N II BIOCHEMISTRY AND C
Page 138 and 139: C H A P T E R 7 Energy metabolism P
Page 140 and 141: SUBCELLULAR ORGANIZATION OF AMITOCH
Page 142 and 143: CELL MEMBRANE Fructose [b] Glucose
Page 144 and 145: STEPS OF AMITOCHONDRIATE CORE METAB
Page 146 and 147: ENZYMATIC DIFFERENCES BETWEEN AMITO
Page 148 and 149: ACTION OF NITROIMIDAZOLE DRUGS 135
Page 150 and 151: ENVOI 137 unambiguously reflect the
Page 152 and 153: FURTHER READING 139 Saavedra-Lira,
Page 156 and 157: THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
Page 164 and 165: WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
Page 166 and 167: FURTHER READING 153 for use in agri
Page 168: CARBOHYDRATE METABOLISM 155 as a hu
Page 171 and 172: 158 ENERGY METABOLISM - APICOMPLEXA
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Page 185 and 186: 172 PROTEIN METABOLISM PROTEINS (1)
Page 187 and 188: 174 PROTEIN METABOLISM the C-termin
Page 189 and 190: 176 PROTEIN METABOLISM and also, to
Page 191 and 192: 178 PROTEIN METABOLISM values rangi
Page 193 and 194: 180 PROTEIN METABOLISM of the plasm
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192 PROTEIN METABOLISM been describ
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194 PROTEIN METABOLISM absence of g
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198 PURINES AND PYRIMIDINES enable
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200 PURINES AND PYRIMIDINES provide
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202 PURINES AND PYRIMIDINES activit
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204 PURINES AND PYRIMIDINES physiol
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206 PURINES AND PYRIMIDINES Amitoch
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208 PURINES AND PYRIMIDINES their a
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210 PURINES AND PYRIMIDINES FIGURE
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214 PURINES AND PYRIMIDINES protein
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220 PURINES AND PYRIMIDINES in Plas
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222 PURINES AND PYRIMIDINES whereas
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226 TRYPANOSOMATID CARBOHYDRATES AF
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228 TRYPANOSOMATID CARBOHYDRATES In
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230 TRYPANOSOMATID CARBOHYDRATES po
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232 TRYPANOSOMATID CARBOHYDRATES LP
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234 TRYPANOSOMATID CARBOHYDRATES re
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236 TRYPANOSOMATID CARBOHYDRATES sc
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A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
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240 TRYPANOSOMATID CARBOHYDRATES Cr
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242 INTRACELLULAR SIGNALING protein
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244 INTRACELLULAR SIGNALING FIGURE
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246 INTRACELLULAR SIGNALING 212.5 2
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248 INTRACELLULAR SIGNALING cycle.
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250 INTRACELLULAR SIGNALING V-H -A
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252 INTRACELLULAR SIGNALING domain)
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254 INTRACELLULAR SIGNALING the kno
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256 INTRACELLULAR SIGNALING from in
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258 INTRACELLULAR SIGNALING FIGURE
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260 INTRACELLULAR SIGNALING ESAG4 (
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262 INTRACELLULAR SIGNALING and ind
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264 INTRACELLULAR SIGNALING ATPase
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266 INTRACELLULAR SIGNALING G11XG
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268 INTRACELLULAR SIGNALING a diffe
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270 INTRACELLULAR SIGNALING rapid l
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272 INTRACELLULAR SIGNALING cells w
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274 INTRACELLULAR SIGNALING PfPPJ i
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276 INTRACELLULAR SIGNALING is cont
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278 PLASTIDS, MITOCHONDRIA, AND HYD
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298 HELMINTH SURFACES Important exc
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300 HELMINTH SURFACES protease inhi
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302 HELMINTH SURFACES volume, there
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304 HELMINTH SURFACES projecting si
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306 HELMINTH SURFACES schistosome t
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308 HELMINTH SURFACES re-establish
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310 HELMINTH SURFACES hepatic cells
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312 HELMINTH SURFACES lungs. Larvae
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314 HELMINTH SURFACES cuticle, whic
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316 HELMINTH SURFACES cuticle in th
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318 HELMINTH SURFACES mec-8 or sym-
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320 HELMINTH SURFACES current, when
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322 HELMINTH SURFACES The cuticle-h
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324 HELMINTH SURFACES are typically
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326 HELMINTH SURFACES or carrier pr
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328 HELMINTH SURFACES of tyrosine-b
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330 HELMINTH SURFACES blood. The ge
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332 HELMINTH SURFACES Mutations in
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334 HELMINTH SURFACES in the hypode
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336 HELMINTH SURFACES (including H-
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338 HELMINTH SURFACES Blaxter, M.L.
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340 ENERGY METABOLISM IN HELMINTHS
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360 NEUROTRANSMITTERS CO 2 H NH 2 G
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362 NEUROTRANSMITTERS TABLE 15.1 An
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364 NEUROTRANSMITTERS more arms tha
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366 NEUROTRANSMITTERS the surroundi
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368 NEUROTRANSMITTERS proteins requ
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370 NEUROTRANSMITTERS FIGURE 15.11
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372 NEUROTRANSMITTERS FIGURE 15.13
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374 NEUROTRANSMITTERS sensitivity t
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376 NEUROTRANSMITTERS TABLE 15.3 Cl
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378 NEUROTRANSMITTERS crossed the c
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380 NEUROTRANSMITTERS have been tes
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382 NEUROTRANSMITTERS C-terminals a
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384 NEUROTRANSMITTERS Davis and Str
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386 NEUROTRANSMITTERS Cephalic gang
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388 NEUROTRANSMITTERS myoexcitation
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390 NEUROTRANSMITTERS is phosphoryl
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392 NEUROTRANSMITTERS many other an
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398 DRUG RESISTANCE of some of the
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400 DRUG RESISTANCE It is now estim
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402 DRUG RESISTANCE is again assume
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404 DRUG RESISTANCE An alternative
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406 DRUG RESISTANCE clinical eviden
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408 DRUG RESISTANCE FIGURE 16.4 Fol
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410 DRUG RESISTANCE Using similar s
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412 DRUG RESISTANCE whether these r
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414 DRUG RESISTANCE FIGURE 16.5 Str
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416 DRUG RESISTANCE FIGURE 16.6 Try
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418 DRUG RESISTANCE has permitted e
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420 DRUG RESISTANCE FIGURE 16.7 Dru
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422 DRUG RESISTANCE near future. Th
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424 DRUG RESISTANCE million new inf
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426 DRUG RESISTANCE some 50 million
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428 DRUG RESISTANCE pharynx, the bo
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430 DRUG RESISTANCE efforts for glo
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432 DRUG RESISTANCE and resistance
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434 MEDICAL IMPLICATIONS TABLE 17.1
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436 MEDICAL IMPLICATIONS TABLE 17.1
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438 MEDICAL IMPLICATIONS transmissi
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440 MEDICAL IMPLICATIONS H 2 C H H
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442 MEDICAL IMPLICATIONS parasites
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444 MEDICAL IMPLICATIONS neuropsych
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446 MEDICAL IMPLICATIONS of toxic f
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448 MEDICAL IMPLICATIONS Future con
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450 MEDICAL IMPLICATIONS Melarsopro
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452 MEDICAL IMPLICATIONS prevention
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454 MEDICAL IMPLICATIONS resulting
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456 MEDICAL IMPLICATIONS for S. ste
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458 MEDICAL IMPLICATIONS are though
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460 MEDICAL IMPLICATIONS FIGURE 17.
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462 MEDICAL IMPLICATIONS Marr, J.J.
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464 INDEX Aldolase, 143 Plasmodium
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466 INDEX Ascofuranone, 143 ASCUT-1
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468 INDEX Cnidarians, RNA trans-spl
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470 INDEX Entamoeba, 125 Ca 2 metab
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472 INDEX Glucose-6-phosphate dehyd
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474 INDEX Ivermectin, 398, 427, 455
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476 INDEX Maduramicin, 412 Major va
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478 INDEX Nitric oxide: neurotransm
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480 INDEX calcium-binding proteins,
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482 INDEX Pyrimidine transport, 200
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484 INDEX Succinate:rhodoquinone ox
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486 INDEX genome, 21 survey sequenc
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488 INDEX U small nuclear RNA (snRN
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