Pathways

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.

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.

Metabolites of Vardenafil are predicted with biotransformer.

The vasopressin V2 receptor is found in the kidneys. It serves a role in maintaining corporal water homeostasis. Malfunction of this receptor can lead to Nephrogenic Diabetes Insipidus. Vasopressin (aka Antidiuretic hormone) activates both follicle-stimulating hormone receptor as well as the V2 receptor G protein complex. From this complex, Guanine nucleotide binding protein G(s) protein reacts with Adenylate Cyclase Type 2, Adeonsine Triphosphate, as well as GTP and magnesium to produce cAMP and Pyrophosphate. cAMP then activates PKA (protein kinase A) which leads to changes in the concentration of water in urine.

The vasopressin V2 receptor is found in the kidneys. It serves a role in maintaining corporal water homeostasis. Malfunction of this receptor can lead to Nephrogenic Diabetes Insipidus. Vasopressin (aka Antidiuretic hormone) activates both follicle-stimulating hormone receptor as well as the V2 receptor G protein complex. From this complex, Guanine nucleotide binding protein G(s) protein reacts with Adenylate Cyclase Type 2, Adeonsine Triphosphate, as well as GTP and magnesium to produce cAMP and Pyrophosphate. cAMP then activates PKA (protein kinase A) which leads to changes in the concentration of water in urine.