Pathways

Metabolites of Vardenafil are predicted with biotransformer.

Vanoxerine is an investigational drug that is a selective dopamine transporter antagonist that has not been approved for therapeutic use but is indicated to help treat cocaine addiction. It was developed as a treatment for depression but was found to have a higher affinity for the dopamine reuptake transporter with a slower dissociation rate than cocaine, indicating its use in cocaine addiction. Vanoxerine does have a moderate potential to be abused by humans as it stimulates the nervous system through the reuptake of norepinephrine and dopamine, which prolongs their duration in the synapse so that they can bind more readily to the receptors. This drug can inhibit cocaine binding sites at the dopamine transporters. The mechanism is not fully understood, but may be similar to other dopamine reuptake inhibitors where Vanoxerine would cross the blood-brain barrier through diffusion. Dopamine is synthesized in the ventral tegmental area of the brain from tyrosine being synthesized into L-dopa by the enzyme Tyrosine 3-monooxygenase . L-Dopa is then synthesized into dopamine with the enzyme aromatic-L-amino-acid decarboxylase. Dopamine then travels to the prefrontal cortex, which is released into the synapse when the neuron is stimulated and fires. Vanoxerine binds to the sodium-dependent dopamine transporter, preventing dopamine from re-entering the presynaptic neuron. The dopamine then binds to Dopamine D4 receptors on the postsynaptic membrane. The dopamine D4 receptor activates the Gi protein cascade which inhibits adenylate cyclase. This prevents adenylate cyclase from catalyzing ATP into cAMP.

The vancomycin resistance pathway in Streptomyces coelicolor primarily confers resistance to glycopeptide antibiotics, such as vancomycin and teicoplanin. These antibiotics aim to inhibit bacterial cell wall synthesis by binding to the D-Ala-D-Ala termini of peptidoglycan precursors. The resistance mechanism involves the alteration of these precursors to D-Ala-D-Lac, which reduces the binding affinity of vancomycin, rendering it ineffective. This modification is mediated by enzymes encoded by the vanHAX operon, which is activated by the VanRS two-component signal transduction system in the presence of vancomycin. The VanRS two-component regulatory system detects antibiotics and induces the operon expression thus conferring resistance to the bacteria. Additionally, novel genes such as vanJ and vanK have been identified within this system, which are essential for the full expression of vancomycin resistance and VanJ and vanK are do not exist in any previously identified vancomycin-resistant pathogen clusters. The van genes are arranged into four transcription units: vanRS, vanJ, vanK, and vanHAX and are orthologous to those seen in vancomycin-resistant enterococci. The vanS gene encodes a sensor kinase protein, which detects vancomycin and autophosphorylates VanR response regulator protein, activating it and enabling it to bind to the promoter to activate transcription. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). A D-Ala-D-Ala dipeptidase, encoded by the vanX gene, hydrolyzes D-Ala-D-Ala dipeptides thus preventing their integration into the peptidoglycan and subsequent peptidoglycan formation in the presence of vancomycin. vanA encodes a D-alanine D-alanine ligase which synthesizes the D-Ala-D-Lac dipeptide that replaces the normal D-Ala-D-Ala in the peptidoglycan precursor, thereby reducing vancomycin's binding affinity.

The VanG-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanG operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 8 genes which can be divided into regulatory (vanU, vanR and vanS), resistance (vanG, vanT and vanXY) and accessory(vanY and vanW). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. Similar to vanR, vanU encodes for a transcriptional activator though not the primary activator. vanG gene encodes a D-Ala-D-Ser ligase, which synthesizes D-Ala-D-Ser (D-alanine-D-serine) dipeptides instead of the usual D-Ala-D-Ala in the peptidoglycan precursor, which has reduced affinity for vancomycin and is added to UDP-MurNAc-tripeptide.vanXY gene encodes a bifunctional D,D-dipeptidase and D,D-carboxypeptidase that hydrolyzes any remaining D-Ala-D-Ala dipeptides and removes D-alanine from peptidoglycan precursors (UDP-MurNAc-pentapeptide[d-Ala]), ensuring that only D-Ala-D-Ser is incorporated into the cell wall. The accessory gene vanY, encodes a D,D-carboxypeptidase that, ensures that only D-Ala-D-Lac is used in cell wall synthesis by eliminating the terminal D-alanine residue from peptidoglycan precursorswhile vanW's function is unknown. Lastly, VanT encodes a serine racemase that is membrane-bound and supplies d-Ser for the synthesis pathway.

The VanE-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanE operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 5 genes which can be divided into regulatory (vanR and vanS) and resistance (vanE, vanXY and vanT). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. The VanE gene encodes D-Ala-D-Lac ligase that synthesizes the D-Ala-D-Lac dipeptide, which replaces the normal D-Ala-D-Ala in the peptidoglycan precursor to which vancomycin has less affinity. vanXY gene encodes a bifunctional D,D-dipeptidase and D,D-carboxypeptidase that hydrolyzes any remaining D-Ala-D-Ala dipeptides and removes D-alanine from peptidoglycan precursors (UDP-MurNAc-pentapeptide[d-Ala]), ensuring that only D-Ala-D-Ser is incorporated into the cell wall. Lastly, VanT encodes a serine racemase that is membrane-bound and supplies d-Ser for the synthesis pathway.

The VanD-type vancomycin resistance pathway enables enterococcal bacteria to resist the action of the glycopeptide antibiotic vancomycin. This pathway involves a series of genes organized in an the VanD operon, which encodes enzymes and regulatory proteins that alter the bacterial cell wall, making it resistant to vancomycin. The operon is made up of 5 genes which can be divided into regulatory (vanR and vanS), resistance (vanH, vanD and vanX) and accessory (vanY). The vanR gene is a response regulator that is part of a two-component regulatory system and activates transcription once phosphorylated by histidine kinase that is encoded by vanS, after detecting vancomycin. vanD gene encodes a D-Ala-D-Lac ligase, synthesizing the D-Ala-D-Lac (D-alanine-D-lactate) dipeptide, replacing the typical D-Ala-D-Ala in the peptidoglycan precursor, which has reduced affinity for vancomycin and is added to UDP-MurNAc-tripeptide. vanX encodes a D,D-dipeptidase that hydrolyzes D-Ala-D-Ala dipeptides, ensuring that only D-Ala-D-Lac is available for incorporation into the peptidoglycan, and subsequent peptidoglycan formation even in the presence of vancomycin. The vanH gene encodes an e D-lactate dehydrogenase, which converts pyruvate to D-lactate, a precursor for the altered peptidoglycan precursor (to counteract the effects of vancomycin, which targets the peptidoglycan by binding to D-alanine-D-alanine terminus of the peptide chains, inhibiting cell wall synthesis). Lastly, the accessory gene vanY, encodes a D,D-carboxypeptidase that, ensures that only D-Ala-D-Lac is used in cell wall synthesis by eliminating the terminal D-alanine residue from peptidoglycan precursors