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MITOCHONDRIAL METABOLISM AND ENERGY GENERATION 345 filariae, convert most of their abundant supplies of environmental glucose to lactate and survive well, at least in the short term, in the absence of oxygen. However, these organisms still contain cristate mitochondria capable of aerobic respiration and may preferentially use carbon derived from amino acids, such as glutamine, as substrates for mitochondrial metabolism. The contribution of aerobic metabolism to these lactate-forming helminths is difficult to quantify, although they do not appear to exhibit a marked Pasteur effect. However, the complete oxidation of glucose to CO 2 is energetically much more efficient than lactate formation (30 vs 2 mol ATP/mol glucose), so that even if only a small percentage of the glucose were oxidized completely, it still could contribute significantly to overall energy generation. In contrast to blood- and tissuedwelling helminths, lumen-dwelling helminths, such as adult A. suum, contain unusual, less cristate mitochondria, which generate a significant portion of their energy anaerobically, by coupling phosphorylation to electron transport associated with the NADH-dependent reduction of fumarate and, in some cases, 2-methyl branched-chain enoyl CoAs. Anaerobic mitochondrial metabolism in helminths Helminths utilizing anaerobic malate dismutation produce a wide range of metabolic endproducts of carbohydrate metabolism, but their mitochondrial pathways are surprisingly similar given their diverse phylogenetic origins. Typically, these organisms operate a portion of the tricarboxylic acid cycle (from oxaloacetate to succinate) and in some cases -oxidation, in a direction opposite to that found in aerobic organisms. In fact, based on the midpoint potentials of the dehydrogenases involved, it is the helminth pathways that function in the energetically preferred direction. Succinate oxidation and -oxidation are only energetically feasible if NAD /NADH ratios are maintained in an oxidized state (10) by a powerful oxidant, such as oxygen. In aerobic organisms, the removal of oxygen causes a rapid accumulation of NADH as the dehydrogenases approach equilibrium, and even ischemic vertebrate heart muscle accumulates succinate through a pathway similar to that operating in the parasitic helminths. In fact, every invertebrate phylum has members capable of anaerobic mitochondrial energy generation, but in most cases this ability is facultative and depends on the availability of oxygen. In the larger parasitic helminths, muscle mitochondria are committed almost exclusively to anaerobic energy generation and do little else. For example, mitochondria from adult A. suum body wall muscle lack functional tricarboxylic acid and urea cycles, are incapable of -oxidation, are limited in their ability to metabolize amino acids and lack significant cytochrome oxidase activity. All helminths capable of anaerobic metabolism use malate as the primary mitochondrial substrate, and the oxidative decarboxylations of first malate and then pyruvate generate intramitochondrial reducing power in the form of NADH (Figure 14.2). In contrast, the pathways used to reoxidize intramitochondrial NADH are quite diverse and depend on the stage or species of helminth under examination, but in all cases, redox balance is maintained and electron-transport-associated ATP is generated by the NADH-reduction of fumarate to succinate. In the cestode H. diminuta, succinate and acetate are the major end-products of anaerobic malate dismutation and are excreted in the predicted 2:1 ratio. In the trematode F. hepatica, succinate is then further decarboxylated to propionate with an additional substratelevel phosphorylation coupled to the decarboxylation of methylmalonyl CoA. F. hepatica BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS
346 ENERGY METABOLISM IN HELMINTHS FIGURE 14.2 Malate metabolism in mitochondria from body wall muscle of adult Ascaris suum. (1) fumarase; (2) malic enzyme; (3) pyruvate dehydrogenase complex; (4) complex I; (5) succinate-coenzyme Q reductase (complex II, fumarate reductase); (6) acyl CoA transferase; (7) methylmalonyl CoA mutase; (8) methylmalonyl CoA decarboxylase; (9) condensing enzyme; (10) 2-methyl acetoacetyl CoA reductase; (11) 2-methyl-3-oxo-acyl CoA hydratase; (12) electron-transfer flavoprotein; (13) 2-methyl branched-chain enoyl CoA reductase; (14) acyl CoA transferase. BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS
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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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ANTIGENIC VARIATION AT THE STRUCTUR
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ANTIGENIC VARIATION AT THE STRUCTUR
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VSG Signal sequence Amino-terminal
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GENETICS OF ANTIGENIC VARIATION 97
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IMMUNE RESPONSES TO TRYPANOSOME INF
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INNATE RESISTANCE, HUMAN SUSCEPTIBI
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ANTIGENIC VARIATION IN MALARIA 107
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FURTHER READING 109 ACKNOWLEDGEMENT
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C H A P T E R 6 Genetic and genomic
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‘FORWARD’ VS. ‘REVERSE’ GEN
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EXAMPLES OF ‘FORWARD’ GENETIC A
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EXAMPLES OF ‘FORWARD’ GENETIC A
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REVERSE GENETICS AND LEISHMANIA VIR
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VALIDATION OF CANDIDATE VIRULENCE G
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S E C T I O N II BIOCHEMISTRY AND C
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C H A P T E R 7 Energy metabolism P
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SUBCELLULAR ORGANIZATION OF AMITOCH
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CELL MEMBRANE Fructose [b] Glucose
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STEPS OF AMITOCHONDRIATE CORE METAB
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ENZYMATIC DIFFERENCES BETWEEN AMITO
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ACTION OF NITROIMIDAZOLE DRUGS 135
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ENVOI 137 unambiguously reflect the
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FURTHER READING 139 Saavedra-Lira,
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
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FURTHER READING 153 for use in agri
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CARBOHYDRATE METABOLISM 155 as a hu
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158 ENERGY METABOLISM - APICOMPLEXA
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172 PROTEIN METABOLISM PROTEINS (1)
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174 PROTEIN METABOLISM the C-termin
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176 PROTEIN METABOLISM and also, to
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178 PROTEIN METABOLISM values rangi
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180 PROTEIN METABOLISM of the plasm
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182 PROTEIN METABOLISM in vivo, in
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184 PROTEIN METABOLISM PROLINE Poly
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186 PROTEIN METABOLISM CO 2 Dec-SAM
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188 PROTEIN METABOLISM a cMDH has b
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190 PROTEIN METABOLISM Urea ARGININ
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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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Page 307 and 308: 294 PLASTIDS, MITOCHONDRIA, AND HYD
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Page 311 and 312: 298 HELMINTH SURFACES Important exc
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Page 315 and 316: 302 HELMINTH SURFACES volume, there
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Page 319 and 320: 306 HELMINTH SURFACES schistosome t
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Page 325 and 326: 312 HELMINTH SURFACES lungs. Larvae
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Page 339 and 340: 326 HELMINTH SURFACES or carrier pr
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Page 349 and 350: 336 HELMINTH SURFACES (including H-
Page 351 and 352: 338 HELMINTH SURFACES Blaxter, M.L.
Page 353 and 354: 340 ENERGY METABOLISM IN HELMINTHS
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Page 373 and 374: 360 NEUROTRANSMITTERS CO 2 H NH 2 G
Page 375 and 376: 362 NEUROTRANSMITTERS TABLE 15.1 An
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Page 379 and 380: 366 NEUROTRANSMITTERS the surroundi
Page 381 and 382: 368 NEUROTRANSMITTERS proteins requ
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Page 395 and 396: 382 NEUROTRANSMITTERS C-terminals a
Page 397 and 398: 384 NEUROTRANSMITTERS Davis and Str
Page 399 and 400: 386 NEUROTRANSMITTERS Cephalic gang
Page 401 and 402: 388 NEUROTRANSMITTERS myoexcitation
Page 403 and 404: 390 NEUROTRANSMITTERS is phosphoryl
Page 405 and 406: 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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