Biochemisty of Drugs as Enzyme Inactivators Flashcards
A mechanism-based enzyme inactivator is
an unreactive compound that bears a structural similarity to the substrate or product for a specific enzyme.
Irreversible inhibitor bond
covalent bond
inactivators that does not form a covalent bond to the enzyme
methotrexate and allopurinol bind so tightly without covalent modification
The advantage of mechanism-based enzyme inactivators lies in the fact that these compounds are
unreactive, thus limiting toxicity and side effects
compounds used to protect penicillin and cephalosporins against bacterial degradation (inactivate bacterial β-lactamases)
Clavulanic acid, sulbactam, and tazobactam
agent reduce high levels of uric acid in gout (inactivates xanthine oxidase)
Allopurinol
an antiparkinson agent (inactivates MAO-B)
L-deprenyl
an anticonvulsant (antiseizure) agent (inactivates GABA-T)
Vigabatrin
a chemotherapy agent (inactivates DHFR)
Methotrexate
an antineoplastic agent for CML and GIST, (inactivates Bcr-Abl p210, c-KIT and PDGFR tyrosine kinases)
Imatinib mesylate
affects NO in pulmonary hypertension (inactivates PDE5)
Sildenafil
anticonvulsant (inactivates HDAC1)
Valproic acid
cancer chemotherapy (Proteosome Inhibitor)
Bortezomib
These inhibitors contain the β-lactam ring, which disguises its role as irreversible inhibitors. The attack by the enzyme on clavulanic acid is the same step as with penicillin (i.e. an acylation reaction). This is followed by a second and lethal step with the inhibitor, the β-elimination, which does not dissociate it from the enzyme.
β-Lactamase Inhibitors
Clinically, the β-lactamase inactivators are used in combination with the _______ for the treatment of __________. Combinations include:
pencillins; penicillin-resistant bacterial infections. amoxicillin/clavulanic acid (Augmentin) ticarcillin/clavulanic acid (Timentin) ampicillin/sulbactam (Unasyn) piperacillin/tazobactam (Zosyn)
Uric acid (UA) in humans is formed by the
xanthine oxidase-catalyzed oxidation of hypoxanthine and xanthine, derived from the hydrolysis of adenine and guanine respectively.
disease with UA in joints
Gout
acute leukemia with high cell turnover (UA breakdown product from DNA). Give allopurinol and hydration during chemotherapy.
Cancer
inhibits the biosynthesis of uric acid
allopurinol
Allopurinol is oxidized by
xanthine oxidase to oxypurinol with the associated reduction of Mo(VI) cofactor to Mo (IV) (the molybdenum pterin active site).
oxypurinol (alloxanthine), is a potent, tight-binding inhibitor of the enzyme, but only when it is in the _____ state
reduced
an anti-parkinson agent
L-deprenyl (selegiline)
a degenerative neurological disease affecting more than a 500,000 in US. Characterized by chronic progressive motor dysfunction resulting in severe “pill rolling” tremors, rigidity, and akinesia.
Parkinson’s disease
Parkinson’s disease arise from the degeneration _______ of and a marked reduction in the concentration of the pyridoxal-5’-phosphate-dependent aromatic ________ , the enzyme that catalyzes the conversion of ________.
dopaminergic neurons in the substantia nigra; L-amino acid decarboxylase; L-dopa to the inhibitory neurotransmitter dopamine.
metabolized (degraded) primarily by monoamine oxidase B (MAO-B) in humans
dopamine
Parkinson’s disease =
reduction in the brain dopamine concentration (substantia nigra)
effective in increasing the dopamine concentration and thus treat the disease (by L-deprenyl
Selective inactivation of MAO-B
an anticonvulsant (anti-seizure) agent
Vigabatrin
any central nervous system disease characterized by recurring convulsive seizures occurring in 0.5-1% of the world population
Epilepsy (seizure disorder)
when no cause for the seizure is known
primary or idiopathic
when the etiology of seizure has been identified
secondary or symptomatic
Symptomatic epilepsy can result from specific diseases or secondary causes
brain tumors, syphilis, cerebral arteriosclerosis, multiple sclerosis, Buerger’s disease, Pick’s disease, Alzheimer’s disease, heat-stroke, acute intoxication, lead poisoning, head trauma, vitamin B-6 deficiency, hypoglycemia, and labor.
seizures occur when there is an imbalance in 2 principal neurotransmitters in the brain, _________ and _________
L-glutamic acid, an excitatory neurotransmitter, and gamma-aminobutyric acid (GABA)
L-glutamic acid, ________neurotransmitter
an excitatory
gamma-aminobutyric acid (GABA), __________ neurotransmitter.
an inhibitory
GABA concentration is regulated ________
by 2 pyridoxal 5’-phosphate (PLP)-dependent enzymes.
2 Pyridoxal 5’-phosphate dependent enzymes
L-glutamic acid decarboxylase (GAD, glutamate decarboxylase): converts glutamate → GABA GABA aminotransferase (GABA-T, 4-aminobutyrate aminotransferase): degrades GABA → succinic semialdehyde which is subsequently converted into succinic acid by the enzyme succinic semialdehyde dehydrogenase (SSADH, succinate semialdehyde dehydrogenase) √ (vigabatrin)
Below a set threshold concentration of GABA level in the brain, ______ occur
seizures Low (inhibitory) GABA = seizure discharges
GABA system dysfunction has been implicated in the symptoms associated with _______
epilepsy,Huntington’s disease, Parkinson’s disease, and tardive dyskinesia.
if GABA is given orally, there is no anticonvulsant effect. Why?
GABA, being polar, cannot cross the blood-brain barrier
the enzyme that catalyzes the degeneration of GABA
GABA-T
Enhancing GABA (inhibitory) in brain of addicts may control ________
drug cravings
Methotrexate Mechanism of Action
Enzyme DHFR is the 1º site of action. MTX inhibits formation of THF (tetrahydrofolate), causing an intracellular deficiency of folate coenzymes and accumulation of the toxic inhibitory substrate, DHF polyglutamate (dihydrofolate). The one carbon transfer reactions for purine and thymidylate synthesis cease (no deoxythymidilate or dTMP), interrupting DNA and RNA synthesis.
MTX Mechanisms of Resistance
Decreased drug transport Altered DHFR (mutation) Decreased polyglutamate formation Increased levels of DHFR
Methotrexate Therapeutic Uses
Inflammatory Diseases (rheumatology): psoriasis, rheumatoid arthritis, SLE (lupus). Oncology: acute lymphoblastic leukemia, meningeal leukemia, choriocarcinoma, osteosarcoma, mycosis fungoides, Burkitt’s and non-Hodgkin’s lymphomas, cancers of the breast, head and neck, ovary, and bladder high dose MTX – followed by leucovorin rescue (bypassing inhibition to minimize side effects)
Methotrexate Side Effects
Wide range of activity in all dosages (oral, IV and high dose). Acute Side Effects: nausea, vomiting, diarrhea, fever, hepatic necrosis, allergy Dose Limiting Toxicity: Oral and GI ulceration (mucositis), bone marrow suppression, pulmonary fibrosis Delayed Toxicities: hepatic/renal toxicity, encephalopathy, conjunctivitis, alopecia, depigmentation
Methotrexate Toxicity Treatment
Bone marrow suppression Rescue with leucovorin (folinic acid) Essential after high dose MTX Nephrotoxic give sodium bicarbonate to alkalinize the urine Effective killing of rapidly dividing cancer cells; also epithelial, hair follicle and BM stem
the 571st signal transduction inhibitor which Novartis worked on to produce a tyrosine kinase inhibitor which works specifically on the intracellular domain of CD117, the c-KIT receptor
Imatinib
Imatinib revolutionized the treatment of _______ and _______
chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST) tumors
caused by immortalization of cellular population due to the Philadelphia chromosome which produces the bcr-abl fusion protein by a balanced translocation between the long arms of chromosomes 9 and 22. T(9,22)
CML (chronic myelogenous leukemia)
imatinib inhibits
Bcr-Abl tyrosine kinase, the constitutive abnormally phosphorylated gene product of the Philadelphia chromosome in CML
Inhibition blocks proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as in
fresh leukemic cells in Philadelphia chromosome positive cell lines
Imatinib blocks
ATP binding
is a cancer with upregulated c-kit
Gastrointestinal stromal tumor (GIST)
Imatinib also inhibits tyrosine kinases for
platelet derived growth factor (PDGF), stem cell factor (SCF), c-kit, and events mediated by PDGF and SCF
Tyrosine kinase inhibitors (TKIs) like imatinib induce
sustained responses in both hematologic and solid malignancies
associated with fewest secondary (or off target side effects)
BCR-ABL1 inhibition
