Pathways

Ponatinib is a tyrosine kinase inhibitor used to treat chronic myelogenous leukemia (CML), a cancer characterized by increased and unregulated growth of white blood cells in the bone marrow and the accumulation of these cells in the blood. The cause of CML pathophysiology is the BCR-ABL fusion protein - the result of a genetic abnormality known as the Philadelphia chromosome in which Abelson Murine Leukemia viral oncogene homolog 1 (ABL1) translocates within the Breakpoint Cluster Region (BCR) gene on chromosome 22. BCR-ABL is a cytoplasm-targeted constitutively active tyrosine kinase that activates several oncogenic pathways which promote increased cell proliferation and survival including the MAPK/ERK Pathway, the JAK-STAT Pathway, and the PI3K/Akt pathway. Ponatinib is considered a third generation BCR-ABL inhibitor (Imatinib being the progenitor) due to its effectiveness against the T315I mutation in BCR-ABL. For greater detail of some of the signalling pathways inhibited by BCR-ABL inhibition, refer to the pathway titled BCR-ABL Action in CML Pathogenesis.

Metabolites of Ponesimod are predicted with biotransformer.

Porphyria variegata (PV) is a rare inborn error of metabolism (IEM) which arises from a defective gene called PPOX. PPOX is responsible for protoporphyrinogen oxidase. A defect in this enzyme results in the build up of several compounds, including porphobilinogen, 5-aminolevulinic acid, and in feces and urine, porphyrin and coproporphyrin. Of the wide range of symptoms which present themselves in affected individuals, some include abdominal pain, vomiting, and diarrhea. As well as seizures, hallucinations and skin sensitivity to light. Indeed, the skin sensitivity can be so extreme that skin pigmentation changes, scarring and blistering and even hair growth can ensue on exposed areas.

Porphyria variegata (PV) is a rare inborn error of metabolism (IEM) which arises from a defective gene called PPOX. PPOX is responsible for protoporphyrinogen oxidase. A defect in this enzyme results in the build up of several compounds, including porphobilinogen, 5-aminolevulinic acid, and in feces and urine, porphyrin and coproporphyrin. Of the wide range of symptoms which present themselves in affected individuals, some include abdominal pain, vomiting, and diarrhea. As well as seizures, hallucinations and skin sensitivity to light. Indeed, the skin sensitivity can be so extreme that skin pigmentation changes, scarring and blistering and even hair growth can ensue on exposed areas.

Porphyria variegata (PV) is a rare inborn error of metabolism (IEM) which arises from a defective gene called PPOX. PPOX is responsible for protoporphyrinogen oxidase. A defect in this enzyme results in the build up of several compounds, including porphobilinogen, 5-aminolevulinic acid, and in feces and urine, porphyrin and coproporphyrin. Of the wide range of symptoms which present themselves in affected individuals, some include abdominal pain, vomiting, and diarrhea. As well as seizures, hallucinations and skin sensitivity to light. Indeed, the skin sensitivity can be so extreme that skin pigmentation changes, scarring and blistering and even hair growth can ensue on exposed areas.

Porphyria variegata (PV) is a rare inborn error of metabolism (IEM) which arises from a defective gene called PPOX. PPOX is responsible for protoporphyrinogen oxidase. A defect in this enzyme results in the build up of several compounds, including porphobilinogen, 5-aminolevulinic acid, and in feces and urine, porphyrin and coproporphyrin. Of the wide range of symptoms which present themselves in affected individuals, some include abdominal pain, vomiting, and diarrhea. As well as seizures, hallucinations and skin sensitivity to light. Indeed, the skin sensitivity can be so extreme that skin pigmentation changes, scarring and blistering and even hair growth can ensue on exposed areas.

The Porphyrin and chlorophyll metabolism happens inside the Arabidopsis thaliana cell. Most of the reaction happen inside the Chloroplast and Mitochondrion. "Porphyrins are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical compound of exclusively theoretical interest. Substituted porphines are called porphyrins. Porphyrins are the conjugate acids of ligands that bind metals to form complexes. The metal ion usually has a charge of 2+ or 3+." (Wikipedia, 2020) "Chlorophyll (also chlorophyl) is any of several related green pigments found in the mesosomes of cyanobacteria and in the chloroplasts of algae and plants. Chlorophyll is essential in photosynthesis, allowing plants to absorb energy from light." (Wikipedia, 2020) Alanine, aspartate and glutamate metabolism, Glycine, serine and threonine metabolism, and Riboflavin metabolism are all related pathways to the Porphyrin and chlorophyll metabolism.

The metabolism of porphyrin begins with with glutamic acid being processed by an ATP-driven glutamyl-tRNA synthetase by interacting with hydrogen ion and tRNA(Glu), resulting in amo, pyrophosphate and L-glutamyl-tRNA(Glu) Glutamic acid. Glutamic acid can be obtained as a result of L-glutamate metabolism pathway, glutamate / aspartate : H+ symporter GltP, glutamate:sodium symporter or a glutamate / aspartate ABC transporter . L-glutamyl-tRNA(Glu) Glutamic acid interacts with a NADPH glutamyl-tRNA reductase resulting in a NADP, a tRNA(Glu) and a (S)-4-amino-5-oxopentanoate. This compound interacts with a glutamate-1-semialdehyde aminotransferase resulting a 5-aminolevulinic acid. This compound interacts with a porphobilinogen synthase resulting in a hydrogen ion, water and porphobilinogen. The latter compound interacts with water resulting in hydroxymethylbilane synthase resulting in ammonium, and hydroxymethylbilane. Hydroxymethylbilane can either be dehydrated to produce uroporphyrinogen I or interact with a uroporphyrinogen III synthase resulting in a water molecule and a uroporphyrinogen III. Uroporphyrinogen I interacts with hydrogen ion through a uroporphyrinogen decarboxylase resulting in a carbon dioxide and a coproporphyrinogen I Uroporphyrinogen III can be metabolized into precorrin by interacting with a S-adenosylmethionine through a siroheme synthase resulting in hydrogen ion, an s-adenosylhomocysteine and a precorrin-1. On the other hand, Uroporphyrinogen III interacts with hydrogen ion through a uroporphyrinogen decarboxylase resulting in a carbon dioxide and a Coproporphyrinogen III. Precorrin-1 reacts with a S-adenosylmethionine through a siroheme synthase resulting in a S-adenosylhomocysteine and a Precorrin-2. The latter compound is processed by a NAD dependent uroporphyrin III C-methyltransferase [multifunctional] resulting in a NADH and a sirohydrochlorin. This compound then interacts with Fe 2+ uroporphyrin III C-methyltransferase [multifunctional] resulting in a hydrogen ion and a siroheme. The siroheme is then processed in sulfur metabolism pathway. Uroporphyrinogen III can be processed in anaerobic or aerobic condition. Anaerobic: Uroporphyrinogen III interacts with an oxygen molecule, a hydrogen ion through a coproporphyrinogen III oxidase resulting in water, carbon dioxide and protoporphyrinogen IX. The latter compound then interacts with an 3 oxygen molecule through a protoporphyrinogen oxidase resulting in 3 hydrogen peroxide and a Protoporphyrin IX Aerobic: Uroporphyrinogen III reacts with S-adenosylmethionine through a coproporphyrinogen III dehydrogenase resulting in carbon dioxide, 5-deoxyadenosine, L-methionine and protoporphyrinogen IX. The latter compound interacts with a meanquinone through a protoporphyrinogen oxidase resulting in protoporphyrin IX. The protoporphyrin IX interacts with Fe 2+ through a ferrochelatase resulting in a hydrogen ion and a ferroheme b. The ferroheme b can either be incorporated into the oxidative phosphorylation as a cofactor of the enzymes involved in that pathway or it can interact with hydrogen peroxide through a catalase HPII resulting in a heme D. Heme D can then be incorporated into the oxidative phosphyrlation pathway as a cofactor of the enzymes involved in that pathway. Ferroheme b can also interact with water and a farnesyl pyrophosphate through a heme O synthase resulting in a release of pyrophosphate and heme O. Heme O is then incorporated into the Oxidative phosphorylation pathway.