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1	Evolution of the Heme Biosynthetic Pathway in Eukaryotic Phototrophs CIHLÁŘ, Jaromír January 2018 (has links) This thesis is devoted to the evolution of the heme biosynthetic pathway in eukaryotic phototrophs with particular emphasis on algae possessing secondary and tertiary red and green derived plastids. Based on molecular biology and bioinformatics approaches it explores the diversity and similarities in heme biosynthesis among different algae. The core study of this thesis describes the heme biosynthesis in Bigelowiella natans and Guillardia theta, algae containing a remnant endosymbiont nucleus within their plastids, in dinoflagellates containing tertiary endosymbionts derived from diatoms called dinotoms, and in Lepidodinium chlorophorum, a dinoflagellate containing a secondary green plastid. The thesis further focusses on new insights in the heme biosynthetic pathway and general origin of the genes in chromerids the group of free-living algae closely related to apicomplexan parasites.
2	Evidence for the physical interaction of endosomes with mitochondria in erythroid cells Kahawita, Tanya. January 2008 (has links) Utilization of iron by hemoglobin-producing cells is highly efficient. The acquisition of iron from plasma requires the binding of diferric transferrin (Tf) to its cognate receptor (Tf-R) on the erythroid cell membrane, followed by internalization of the Tf - Tf-R complexes via receptor-mediated endocytosis. Through a poorly understood mechanism, iron is targeted to mitochondria, the site of heme biosynthesis. We believe that a direct interaction between iron-containing endosomes and mitochondria is essential for iron transfer to mitochondria and its efficient incorporation into heme. / In order to illustrate the interaction between endosomes and mitochondria, we have employed flow cytometry. Flow cytometry analysis of reticulocytes (erythrocyte precursors which still synthesize hemoglobin) stained with fluorescent dyes specific to mitochondria and endosomes revealed three distinct populations: mitochondria, endosomes and a population labeled with both dyes. This double-labeled population suggests a population composed of endosomes associated with mitochondria. Using non-fluorescent diferric-Tf, we were able to remove the double population, leaving only the endosomal and the mitochondrial population. This finding has confirmed that the double population is the result of the interaction between the two organelles. / Additionally, we established a cell-free assay consisting of fluorescent mitochondria and endosomes isolated from erythroid cells. Using confocal microscopy, we demonstrated a colocalization between the two organelles. We repeated the assay using fluorescent mitochondria and endosomes isolated from HeLa spinner cells. Using the mitochondrial uncoupler CCCP, we were able to significantly reduce the colocalization between the two organelles, indicating that the interaction between the organelles is specific and that the mitochondrial potential is a requirement for organellar interaction. / Based on our results from flow cytometry and confocal microscopy, we conclude that a specific and direct interaction exists between the two organelles. Heme -- biosynthesis. Iron -- metabolism. Reticulocytes -- metabolism. Endosomes -- metabolism. Mitochondria -- metabolism.
3	An ABCB10 cell-free system and the exploration of its substrates and regulators Qiu, Wei 12 March 2016 (has links) ABCB10, or ATP binding cassette sub-family B member 10, is a protein localized in the mitochondrial inner membrane. It belongs to the ABC transporter family whose members are proteins that facilitate substrate transport across various biological membranes. It has been found that ABCB10 is required for normal heme biosynthesis during erythroid differentiation and also plays a role in protection against the damage caused by reactive oxygen species (ROS) production. This protective effect exists both in the erythrocyte development and in the heart recovery after the ischemia-reperfusion injury. However, as an ABC transporter, its transported substrates are not known, neither is the mechanism by which ABCB10 plays a role in protection against ROS damage. In this dissertation an 8-azido-ATP photolabeling system is established to study the ATP binding and hydrolysis properties of ABCB10. Using this approach, it is found that the conserved amino acid residues Gly497 and Lys498 in the Walker A motif of the nucleotide binding domain of ABCB10 are required for ATP binding. On the other hand, Gly602 in the C-loop motif and Glu624 in the end of the Walker B motif are necessary for ATP hydrolysis. In addition, most ABC transporters increase ATP hydrolysis in the presence of their substrates. Therefore, the 8-azido-ATP photolabeling system can be utilized to test potential substrates of ABCB10. Substances related to the heme biosynthesis such as δ-aminolevulinic acid (dALA) and the mitochondrial redox state such as oxidized glutathione (GSSG) and reduced glutathione (GSH) are tested for this purpose. The 8-azido-ATP photolabeling system shows that GSSG stimulates ATP hydrolysis without affecting ATP binding, whereas GSH decreases ATP binding. Further study shows that the nucleotide binding domain of ABCB10 is glutathionylated at the cysteine residue on the position 547 (Cys547), suggesting that GSH may modulate ABCB10 activity via the glutathionylation-regulated ATP binding. This is a first insight into the molecular mechanism by which the mitochondrial redox state, through the regulation by GSH and GSSG, can modulate ABCB10 activity. / 2016-09-01T00:00:00Z Molecular biology 8-azido-ATP ABCB10 ABC transporter Heme biosynthesis Mitochondria Reactive oxygen species
4	Dual Sites For Heme Biosynthesis In The Malarial Parasite Varadharajan, S 10 1900 (has links) (PDF) No description available. Malaria Heme Biosynthesis Malarial Parasite Ferrochelatase Plasmodium falclparum P. falciparum C5 Pathway Heme Synthesis Biochemistry
5	Evidence for the physical interaction of endosomes with mitochondria in erythroid cells Kahawita, Tanya. January 2008 (has links) No description available. Endosomes -- metabolism. Mitochondria -- metabolism. Iron -- metabolism. Heme -- biosynthesis. Reticulocytes -- metabolism.
6	Unique Features Of Heme-Biosynthetic Pathway In The Human Malaria Parasite, Plasmodium Falciparum Arun Nagaraj, V 07 1900 (has links) Malaria is a life-threatening vector borne infectious disease caused by protozoan parasites of the genus Plasmodium. More than 100 species of Plasmodium can infect numerous animal species such as reptiles, birds and various mammals. However, human malaria is caused by four Plasmodium species -Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae, and occasionally by the simian malaria parasite, Plasmodium knowlesi. Of these, P. falciparum and P. vivax are the major causative agents and P. falciparum is the most virulent. About 300-500 million malaria infections occur every year leading to over 1-2 million deaths, of which 75% occur in African children of less than 5 years infected with P. falciparum. In spite of major global efforts to eliminate this disease over the past few decades, it continues to persist as a major affliction of human-kind imposing serious health and economic burden, especially to the poor countries. In India, the present scenario is about 2 million malaria positive cases every year, with almost 50% being caused by P. falciparum. Although remarkable attempts have been made over the years to develop vaccines against sexual and asexual stages of malaria parasite, an effective vaccine is still not in sight and remains as a distant goal. Hence, highly potent, less toxic and affordable antimalarial drugs remain as a first line therapy for malaria. Unfortunately, these parasites have been evolving against every known antimalarial drug and many of these drugs have lost their potency due to rapid emergence and spread of drug resistant strains. With development of resistance against frontline antimalarials such as chloroquine and antifolates, artemisinin and its derivatives seem to be the only effective antimalarials. However, recent reports on the possible emergence of artemisinin resistant strains, have led to the implementation of artemisinin-based combination therapies as a strategy to prevent drug resistance. Also, this continuous emergence of drug resistance has necessitated the development of new antimalarial drugs to combat this disease. While, Anopheles mosquitoes transmit parasites that infect humans, monkeys and rodents, Culex and Aedes mosquitoes predominate in the natural transmission to birds, and vectors of reptilian parasites are largely unknown. Of the approximately 400 species of Anopheles throughout the world, about 60 are malaria vectors under natural conditions, and 30 of which are of major importance. Ironically, the strategies implemented for controlling Anopheles, have also been hampered by insecticide resistance and other practical difficulties that exist in the scope of their applicability. In the past few years several milestones have been achieved in parasite genome, transcriptome and proteome studies, which could be exploited for the development of new drugs and drug targets. One such promising target includes the metabolic pathways of the malaria parasite which differ significantly from its human host. This thesis entitled “Unique Features of the Heme-Biosynthetic Pathway in Human Malaria Parasite, Plasmodium falciparum” unravels the unique biochemical features of heme-biosynthetic enzymes of P. falciparum, which have the potential for being drug targets. This pathway was first identified in this laboratory over 15 years ago. In the present study, five of the 7 enzymes of this pathway have been cloned, expressed, properties studied and sites of localization identified. With the knowledge on the first two enzymes coming from earlier studies, it is now possible to depict the unique hybrid pathway for heme biosynthesis in P. falciparum with full experimental validation. Malaria Plasmodium Falciparum Heme Biosynthesis Malaria - Drug Resistance Heme Biosynthetic Enzymes Antimalarial Drugs Malaria Drugs Malarial Parasite Ferrochelatase Heme-Biosynthetic Pathway Biochemistry
7	Investigating the porphyrias through analysis of biochemical pathways. Ruegg, Evonne Teresa Nicole January 2014 (has links) ABSTRACT The porphyrias are a diverse group of metabolic disorders arising from diminished activity of enzymes in the heme biosynthetic pathway. They can present with acute neurovisceral symptoms, cutaneous symptoms, or both. The complexity of these disorders is demonstrated by the fact that some acute porphyria patients with the underlying genetic defect(s) are latent and asymptomatic while others present with severe symptoms. This indicates that there is at least one other risk factor required in addition to the genetic defect for symptom manifestation. A systematic review of the heme biosynthetic pathway highlighted the involvement of a number of micronutrient cofactors. An exhaustive review of the medical literature uncovered numerous reports of micronutrient deficiencies in the porphyrias as well as successful case reports of treatments with micronutrients. Many micronutrient deficiencies present with symptoms similar to those in porphyria, in particular vitamin B6. It is hypothesized that a vitamin B6 deficiency and related micronutrient deficiencies may play a major role in the pathogenesis of the acute porphyrias. In order to further investigate the porphyrias, a computational model of the heme biosynthetic pathway was developed based on kinetic parameters derived from a careful analysis of the literature. This model demonstrated aspects of normal heme biosynthesis and illustrated some of the disordered biochemistry of acute intermittent porphyria (AIP). The testing of this model highlighted the modifications necessary to develop a more comprehensive model with the potential to investigated hypotheses of the disordered biochemistry of the porphyrias as well as the discovery of new methods of treatment and symptom control. It is concluded that vitamin B6 deficiency might be the risk factor necessary in conjunction with the genetic defect to trigger porphyria symptoms. Acute attack Acute intermittent porphyria Aminolevulinate Aminolevulinate dehydratase Aminolevulinate synthase B vitamins Biomodeling Cofactors Computational modeling Congenital erythopoietic porphyria Coproporphyrinogen oxidase Erythropoietic protoporphyria Ferrochelatase GABA Glucose therapy Glycine Heme Heme biosynthesis Heme deficiency Heme therapy Hepatoerythropoietic porphyria Hepatorenal Tyrosemia Hereditary coproporphyria Iron Iron deficiency anemia Kinetics Lead poisoning Liver transplant Micronutrients PLP Porphobilinogen Porphobilinogen deaminase Porphyria Porphyria cutanea tarda Porphyrins Prophylaxis Protoporphyrinogen oxidase Pyridoxal Pyridoxal phosphate Pyridoxine Serotonin Succinyl-CoA TCA cycle Tryptophan Tryptophan pyrrolase Uroporphyrinogen decarboxylase Uroporphyrinogen synthase Variegate porphyria Vitamin B6 Vitamin therapy Vitamins X-linked protoporphyria X-linked sideroblastic anemia

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