Porphyrin biosynthesis in parasitic hemoflagellates: Functional and defective enzymes in Trypanosoma cruzi

Salzman, Teresa A.; Stella, Ana María; Xifra, Eva A.Wider De; Batlle, Alcira; Docampo, Roberto; Stoppani, A. O. M.

doi:10.1016/0305-0491(82)90523-5

Cited by 33 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transfection of Leishmania with pbgd alone was originally expected to produce the desired phenotype, because PBGD was thought to be the only enzyme that is deficient in this group of protozoa and supplied to several Crithidia species by their endosymbionts (5). Because ␦-aminolevulinate synthase activity was detected previously in Leishmania (7,8) and other trypanosomatids (6), additional transfection of these organisms with alad would be expected to provide the first three enzymes of the pathway sufficient to produce, at the very least, one or more of the porphyrin intermediates if not heme as the final product (see Table I). However, the double transfectants produced porphyrins only when ALA was supplied exogenously (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier biochemical studies of trypanosomatid protozoa have shown that they are deficient in heme biosynthesis (3,(5)(6)(7)(8). This was examined according to the following conventional pathway: glycine ϩ succinyl-CoA or 4,5-dioxovalerate ϩ alanine 3 ␦-aminolevulinate (ALA) 1 3 porphobilinogen 3 hydroxymethylbilane (by-product ϭ uroporphyrinogen I) 3uroporphyrinogen III 3 co-proporphyrinogen III3 protoporphyrinogen IX3 protoporphyrin IX3 heme (9).…”

mentioning

confidence: 99%

“…Much less or absent are activities of the second and the third enzymes, i.e. ␦-aminolevulinate dehydratase (ALAD, EC 4.2.1.24) and porphobilinogen deaminase (PBGD, EC 4.3.1.8) (3,(5)(6)(7). The pathway thus appears to be incomplete in this group of organisms (3,6).…”

mentioning

confidence: 99%

“…␦-aminolevulinate dehydratase (ALAD, EC 4.2.1.24) and porphobilinogen deaminase (PBGD, EC 4.3.1.8) (3,(5)(6)(7). The pathway thus appears to be incomplete in this group of organisms (3,6). Endosymbionts are thought to complement this incomplete pathway in their Crithidia host by supplying the missing enzymes, i.e.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Genetic Rescue of Leishmania Deficiency in Porphyrin Biosynthesis Creates Mutants Suitable for Analysis of Cellular Events in Uroporphyria and for Photodynamic Therapy

Sah¹,

Ito²,

Kolli³

et al. 2002

Journal of Biological Chemistry

116

View full text Add to dashboard Cite

Leishmania was found deficient in at least five and most likely seven of the eight enzymes in the heme biosynthesis pathway, accounting for their growth requirement for heme compounds. The xenotransfection of this trypanosomatid protozoan led to their expression of the mammalian genes encoding ␦-aminolevulinate (ALA) dehydratase and porphobilinogen deaminase, the second and the third enzymes of the pathway, respectively. These transfectants still require hemin or protoporphyrin IX for growth but produce porphyrin when ALA was supplied exogenously. Leishmania is thus deficient in all first three enzymes of the pathway. Uroporphyrin I was produced as the sole intermediate by these transfectants, further indicating that they are also deficient in at least two porphyrinogen-metabolizing enzymes downstream of porphobilinogen deaminase, i.e. uroporphyrinogen III co-synthase and uroporphyrinogen decarboxylase. Pulsing the transfectants with ALA induced their transition from aporphyria to uroporphyria. Uroporphyrin I emerged in these cells initially as diffused throughout the cytosol, rendering them sensitive to UV irradiation. The porphyrin was subsequently sequestered in cytoplasmic vacuoles followed by its release and accumulation in the extracellular milieu, concomitant with a reduced photosensitivity of the cells. These events may represent cellular mechanisms for disposing soluble toxic waste from the cytosol. Monocytic tumor cells were rendered photosensitive by infection with uroporphyric Leishmania, suggestive of their potential application for photodynamic therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Genetic Rescue of Leishmania Deficiency in Porphyrin Biosynthesis Creates Mutants Suitable for Analysis of Cellular Events in Uroporphyria and for Photodynamic Therapy

Sah¹,

Ito²,

Kolli³

et al. 2002

Journal of Biological Chemistry

116

View full text Add to dashboard Cite

show abstract

“…1). Of these eight enzymes, only the last one, i. e. ferrochelatase (Fe-C) has been shown to exist functionally by nutritional studies (Chang et al, 1975) and enzyme assays (Salzman et al, 1982) in different trypanosomatid protozoa. Most recently, we have found the putative Fe-C sequences of high homology in all Leishmania isolates grouped phylogenetically into some 20 genotypes, including most Old World species, i. e. L. infantum /donovani, L. major, L. tropica, L. turanica and L. gerbilli (Waki et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Leishmania spp.: Delta-aminolevulinate-inducible neogenesis of porphyria by genetic complementation of incomplete heme biosynthesis pathway

Dutta

Furuyama

Sassa

et al. 2008

Experimental Parasitology

View full text Add to dashboard Cite

To further develop the Leishmania model for porphyria based on their deficiencies in heme biosynthesis, three Old World species were doubly transfected as before for Leishmania amazonensis with cDNAs, encoding the 2 nd and 3 rd enzymes in the pathway. Expression of the transgenes was verified immunologically at the protein level and functionally by uroporphyrin neogenesis that occurs only after exposure of the double-transfectants to delta-aminolevulinate. All species examined were equally deficient in heme biosynthesis, as indicated by the accumulation of uroporphyrin as the sole porphyrin and the production of coproporphyrin upon further transfection of one representative species with the downstream gene. The results obtained thus demonstrate that at least the first five enzymes for heme biosynthesis are absent in all species examined, rendering their transfectants inducible with aminolevulinate to accumulate porphyrins and thus useful as cellular models for human porphyrias.

show abstract

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux

Ferreira

Oliveira

Paes

et al. 2018

Cell Biology International

View full text Add to dashboard Cite

Hematophagous organisms undergo remarkable metabolic changes during the blood digestion process, increasing fermentative glucose metabolism, and reducing respiratory rates, both consequence of functional mitochondrial remodeling. Here, we review the pathways involved in energy metabolism and mitochondrial functionality in a comparative framework across different hematophagous species, and consider how these processes regulate redox homeostasis during blood digestion. The trend across distinct species indicate that a switch in energy metabolism might represent an important defensive mechanism to avoid the potential harmful interaction of oxidants generated from aerobic energy metabolism with products derived from blood digestion. Indeed, in insect vectors, blood feeding transiently reduces respiratory rates and oxidant production, irrespective of tissue and insect model. On the other hand, a different scenario is observed in several unrelated parasite species when exposed to blood digestion products, as respiratory rates reduce and mitochondrial oxidant production increase. The emerging picture indicates that re-wiring of energy metabolism, through reduced mitochondrial function, culminates in improved tolerance to redox insults and seems to represent a key step for hematophagous organisms to cope with the overwhelming and potentially toxic blood meal.

show abstract

Porphyrin biosynthesis in parasitic hemoflagellates: Functional and defective enzymes in Trypanosoma cruzi

Cited by 33 publications

References 20 publications

Genetic Rescue of Leishmania Deficiency in Porphyrin Biosynthesis Creates Mutants Suitable for Analysis of Cellular Events in Uroporphyria and for Photodynamic Therapy

Genetic Rescue of Leishmania Deficiency in Porphyrin Biosynthesis Creates Mutants Suitable for Analysis of Cellular Events in Uroporphyria and for Photodynamic Therapy

Leishmania spp.: Delta-aminolevulinate-inducible neogenesis of porphyria by genetic complementation of incomplete heme biosynthesis pathway

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux

Contact Info

Product

Resources

About