Quantitative metabolomics services for biomarker discovery and validation.
Specializing in ready to use metabolomics kits.
Your source for quantitative metabolomics technologies and bioinformatics.
You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on Small Molecule Pathway Database.

Pathways

Showing 1 - 10 of 404 pathways
SMPDB ID Pathway Chemical Compounds Proteins

SMP00107

Pw000270 View Pathway
drug action

Zoledronate Action Pathway

Homo sapiens
The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

SMP00747

Pw000724 View Pathway
drug action

Zidovudine Action Pathway

Homo sapiens
Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA.

SMP00746

Pw000723 View Pathway
drug action

Zalcitabine Action Pathway

Homo sapiens
Zalcitabine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Within cells, zalcitabine is converted to its active metabolite, dideoxycytidine 5'-triphosphate (ddCTP), by the sequential action of cellular enzymes. ddCTP interferes with viral RNA-directed DNA polymerase (reverse transcriptase) by competing for utilization of the natural substrate deoxycytidine 5'-triphosphate (dCTP), as well as incorpating into viral DNA.

SMP00279

Pw000301 View Pathway
drug action

Ximelagatran Action Pathway

Homo sapiens
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.

SMP00268

Pw000311 View Pathway
drug action

Warfarin Action Pathway

Homo sapiens
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.

SMP00439

Pw000244 View Pathway
drug action

Vinorelbine Action Pathway

Homo sapiens
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.

SMP00438

Pw000243 View Pathway
drug action

Vindesine Action Pathway

Homo sapiens
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.

SMP00437

Pw000242 View Pathway
drug action

Vincristine Action Pathway

Homo sapiens
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.

SMP00436

Pw000241 View Pathway
drug action

Vinblastine Action Pathway

Homo sapiens
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.

SMP00375

Pw000390 View Pathway
drug action

Verapamil Action Pathway

Homo sapiens
Verapamil is a phenylalkylamine calcium channel blocker (CCB) or antagonist. There are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type. CCBs target L-type calcium channels, the major channel in muscle cells that mediates contraction. Verapamil, an organic cation, is thought to primarily block L-type calcium channels in their open state by interfering with the binding of calcium ions to the extracellular opening of the channel. It is one of only two clinically used CCBs that are cardioselective. Verapamil and diltiazem and, the other cardioselective CCB, shows greater activity against cardiac calcium channels than those of the peripheral vasculature. Other CCBs, such as nifedipine and amlodipine, have little to no effect on cardiac cells (cardiac myocytes and cells of the SA and AV nodes). Due to its cardioselective properties, verapamil may be used to treat arrhythmias (e.g. atrial fibrillation) as well as hypertension. The first part of this pathway depicts the pharmacological action of verapamil on cardiac myocytes and peripheral arterioles and coronary arteries. Verapamil decreases cardiac myocyte contractility by inhibiting the influx of calcium ions. Calcium ions entering the cell through L-type calcium channels bind to calmodulin. Calcium-bound calmodulin then binds to and activates myosin light chain kinase (MLCK). Activated MLCK catalyzes the phosphorylation of the regulatory light chain subunit of myosin, a key step in muscle contraction. Signal amplification is achieved by calcium-induced calcium release from the sarcoplasmic reticulum through ryanodine receptors. Inhibition of the initial influx of calcium decreases the contractile activity of cardiac myocytes and results in an overall decreased force of contraction by the heart. Verapamil affects smooth muscle contraction and subsequent vasoconstriction in peripheral arterioles and coronary arteries by the same mechanism. Decreased cardiac contractility and vasodilation lower blood pressure. The second part of this pathway illustrates the effect of calcium channel antagonism on the cardiac action potentials. Contractile activity of cardiac myocytes is elicited via action potentials mediated by a number of ion channel proteins. During rest, or diastole, cells maintain a negative membrane potential; i.e. the inside of the cell is negatively charged relative to the cells’ extracellular environment. Membrane ion pumps, such as the sodium-potassium ATPase and sodium-calcium exchanger (NCX), maintain low intracellular sodium (5 mM) and calcium (100 nM) concentrations and high intracellular potassium (140 mM) concentrations. Conversely, extracellular concentrations of sodium (140 mM) and calcium (1.8 mM) are relatively high and extracellular potassium concentrations are low (5 mM). At rest, the cardiac cell membrane is impermeable to sodium and calcium ions, but is permeable to potassium ions via inward rectifier potassium channels (I-K1), which allow an outward flow of potassium ions down their concentration gradient. The positive outflow of potassium ions aids in maintaining the negative intracellular electric potential. When cells reach a critical threshold potential, voltage-gated sodium channels (I-Na) open and the rapid influx of positive sodium ions into the cell occurs as the ions travel down their electrochemical gradient. This is known as the rapid depolarization or upstroke phase of the cardiac action potential. Sodium channels then close and rapidly activated potassium channels such as the voltage-gated transient outward delayed rectifying potassium channel (I-Kto) and the voltage-gated ultra rapid delayed rectifying potassium channel (I-Kur) open. These events make up the early repolarization phase during which potassium ions flow out of the cell and sodium ions are continually pumped out. During the next phase, known as the plateau phase, calcium L-type channels (I-CaL) open and the resulting influx of calcium ions roughly balances the outward flow of potassium channels. During the final repolarization phase, the voltage-gated rapid (I-Kr) and slow (I-Ks) delayed rectifying potassium channels open increasing the outflow of potassium ions and repolarizing the cell. The extra sodium and calcium ions that entered the cell during the action potential are extruded via sodium-potassium ATPases and NCX and intra- and extracellular ion concentrations are restored. In specialized pacemaker cells, gradual depolarization to threshold occurs via funny channels (I-f). Blocking L-type calcium channels decreases conduction and increases the refractory period. Verapamil’s effects on pacemaker cells enable its use as a rate-controlling agent in atrial fibrillation.
Showing 1 - 10 of 404 pathways