Browsing pathways

Vinblastine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinblastine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinblastine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinblastine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinblastine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinblastine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vincristine, a vinca alkaloid isolated from the leaves of the periwinkle plant _Catharanthus roseus_, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vincristine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vincristine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vincristine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vincristine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vincristine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vindesine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vindesine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vindesine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vindesine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vindesine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vindesine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vinorelbine, a semisynthetic vinca alkaloid, is an antimitotic anticancer agent. Its main mechanism of action is thought to be inhibition of microtubule dynamics, which results in mitotic arrest and eventual cell death. Vinorelbine is a microtubule destabilizing agent. At high concentrations, it stimulates microtubule depolymerization and mitotic spindle destruction. At lower clinically relevant concentrations, vinorelbine blocks mitotic progression. Its main targets are tubulin and microtubules. Unlike the taxanes, which bind poorly to soluble tubulin, vinorelbine can bind both soluble and microtubule-associated tubulin. Rapid and reversible binding to soluble tubulin induces a conformational change that increases the affinity of tubulin for itself. This is thought to play a key role in the kinetics of microtubule stabilization. Vinorelbine binds to β-tubulin subunits at the positive end of microtubules at a region called the _Vinca_-binding domain. Binding of just one or two molecules of vinorelbine greatly reduces the rate of microtubule dynamics (lengthening and shortening) and increases the time microtubules spend in an attenuated state. This prevents proper assembly of the mitotic spindle and reduces the tension at the kinetochores of the chromosomes. Subsequently, chromosomes at the spindle poles are unable to progress to the spindle equator. Progression from metaphase to anaphase is blocked and cells enter a state of mitotic arrest. The cells may then undergo one of several fates. The tetraploid cell may undergo unequal cell division producing aneuploid daughter cells. Alternatively, it may exit the cell cycle without undergoing cell division, a process termed mitotic slippage or adaptation. These cells may continue progressing through the cell cycle as tetraploid cells (Adaptation I), may exit G1 phase and undergo apoptosis or senescence (Adaption II), or may escape to G1 and undergo apoptosis during interphase (Adaptation III). Another possibility is cell death during mitotic arrest. Alternatively, mitotic catastrophe may occur and cause cell death. Vinca alkaloids are also thought to increase apoptosis by increasing concentrations of p53 (cellular tumor antigen p53) and p21 (cyclin-dependent kinase inhibitor 1) and by inhibiting Bcl-2 activity. Increasing concentrations of p53 and p21 lead to changes in protein kinase activity. Phosphorylation of Bcl-2 subsequently inhibits the formation Bcl-2-BAX heterodimers. This results in decreased anti-apoptotic activity. One way in which cells have developed resistance against the vinca alkaloids is by drug efflux. Drug efflux is mediated by a number of multidrug resistant transporters as depicted in this pathway.

Vitamin A deficiency can be caused by many causes. A defect in the BCMO1 gene which codes for beta,beta-carotene 15,15'-monooxygenase is one of them. Beta,beta-carotene 15,15'-monooxygenase catalyzes the chemical reaction where the two substrates are beta-carotene and O2, whereas its product is retinal. A defect in this enzyme results in decrease of levels of retinal and vitamin A in serum; Signs and symptoms include night blindness, poor adaptation to darkness, dry skin and hair.

Vitamin B6 is a water-soluble vitamin and is part of the vitamin B complex group. Pyridoxal phosphate (PLP) is the active form of vitamin B6 and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. Seven forms of this vitamin are known: pyridoxine (PN), pyridoxine 5'-phosphate (PNP). pyridoxal (PL), pyridoxal 5'-phosphate (PLP), pyridoxamine (PM), pyridoxamine 5'-phosphate (PMP) and 4-pyridoxic acid (PA). PA is the catabolite which is excreted in the urine. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their dephosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated forms of vitamin B6 in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue. Several products of vitamin B6 metabolism are excreted in the urine including 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6 is oxidized to 4-pyridoxic acid. Other products of vitamin B6 metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates.

Vitamin K describes a group of lipophilic, hydrophobic vitamins that exist naturally in two forms (and synthetically in three others): vitamin K1, which is found in plants, and vitamin K2, which is synthesized by bacteria. Vitamin K is an important dietary component because it is necessary as a cofacter in the activation of vitamin K dependent proteins. Metabolism of vitamin K occurs mainly in the liver. In the first step, vitamin K is reduced to its quinone form by a quinone reductase such as NAD(P)H dehydrogenase. Reduced vitamin K is the form required to convert vitamin K dependent protein precursors to their active states. It acts as a cofactor to the integral membrane enzyme vitamin K-dependent gamma-carboxylase (along with water and carbon dioxide as co-substrates), which carboxylates glutamyl residues to gamma-carboxy-glutamic acid residues on certain proteins, activating them. Each converted glutamyl residue produces a molecule of vitamin K epoxide, and certain proteins may have more than one residue requiring carboxylation. To complete the cycle, the vitamin K epoxide is returned to vitamin K via the vitamin K epoxide reductase enzyme, also an integral membrane protein. The vitamin K dependent proteins include a number of important coagulation factors, such as prothrombin. Thus, warfarin and other coumarin drugs act as anticoagulants by blocking vitamin K epoxide reductase. _

Warfarin is an anticoagulant that inhibits the liver enzyme vitamin K reductase. This leads to the depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulation factors (II, VII, IX, and X), this ultimately results in reduced cleavage of fibrinogen into fibrin and decreased coagulability of the blood.

Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase, which causes accumulation of xanthine in plasma; uric acid in serum; and hypoxanthine, uric acid and xanthine in urine. Symptoms include arthralgia, hematuria, mental retardation, stomatisis, and urolithiasis.

Ximelagatran was the first member of the drug class of direct thrombin inhibitors that can be taken orally. It acts solely by inhibiting the actions of thrombin. Ximelagatran is a prodrug, being converted in vivo to the active agent melagatran.