Integration Flashcards
Pelvic inflammatory disease caused by
Neisseria gonnorhea and
Chlamydia trachomatis
infectious and inflammatory disorder of the upper female genital tract, including the uterus, fallopian tubes, and adjacent pelvic structures
Pelvic inflammatory disease
What is the biochemical mechanism of action of the quinolone
Inhibits DNA gyrase
Enzymes that assist in formation of superhelicesand regulate the breaking and rejoining of the DNA chain
Topoisomerase
interfere with bacterial DNA synthesis
Fluoroquinolones
blocks relaxation of supercoiledDNA
topoisomeraseII (DNA gyrase) in gram-negative organisms
interferes with the separation of replicated chromosomal DNA during cell division
Topoisomerase IV in gram positive
usually bactericidal against susceptible organisms •exhibit postantibioticeffect
Fluoroquinolones
1st generation
Nalidixicacid,
Cinaxacin,
Rosoxacin
2nd generation
Ciprofloxacin,
Ofloxacin,
Norfloxacin
3rd generation
Levofloxacin,
Sparfloxacin,
Grepafloxacin
3rd generation
Levofloxacin,
Sparfloxacin,
Grepafloxacin
4th generation
Moxifloxacin,
Trovafloxacin,
Gemifloxacin,
Gatifloxacin
urinary tract infections
1st generation
gram negatives, gonococci, gram positive cocciand Mycoplasma
2nd generation
less gram negative and more gram positive activity, streptococci and enterococci
3rd generation
broad spectrum, including anaerobes–with increasing generation, increasing gram positive activity
4th generation
increasing generation leads to increasing gram negative activity
Cephalosporin
Inhibits DNA replication bybinding to DNA gyraseand topoisomerase IV. Bactericidal
Ciproploxacin
Ciprofoxacin toxicity
Tendinitis and tendon rupture
FloroquinoLONES hurt attachment to your
Bones
Cartilage damage
As the two strands of the double helix are separated, a problem is encountered, namely
Positive super coils
Supertwist
Theaccumulating positive supercoils interfere with further unwinding of the
Double helix
If the cord is twisted in the direction of tightening the coils, the cord will wrap around itself in space to form
Positive super coils
If the cord is twisted in the direction of loosening the coils, the cord will wrap around itself in the opposite direction to form
Negative supercoils
which are responsible for removing supercoils in the helix
DNA topoisomerase
These enzymes reversibly cut one strand of the double helix
DNA topoisomerase 1
Nuclease and ligase
Strand cutting
Strand resealing
DNA topoisomerase 1 They do not require ATP, but rather appear to store the energy from the
Phopodiester bond
Type I topoisomerasesrelax negative supercoils in ________, and both negative and positive supercoils in ____________
E. coli
Eukaryotic cell
These enzymes bind tightly to the DNA double helix and make transient breaks in both strands
DNAtopoisomearse 2
The enzyme then causes a second stretch of the DNA double helix to pass through the break and, finally, reseals the break
DNA topoisomerase 2
Type II DNA topoisomerasesare also required in both prokaryotes and eukaryotes for the separation of interlocked molecules of DNA following
Chromosomal replication
a Type II topoisomerase found in bacteria and plants, has the unusual property of being able to introduce negative supercoils into relaxed circular DNA using energy from the hydrolysis of ATP
DNA gyrase
Bacterial DNA gyraseis a unique target of a group of antimicrobial agents
Quinolones
A typical human cell contains 46 chromosomes, whose total DNA is approximately
1m long
interaction of DNA with a large number of proteins, each of which performs a specific function in the ordered packaging of these long molecules of DNA
Histones
Eukaryotic DNA is associated with tightly bound basic proteins, called
Histones
DNA into basic structural units
Nucleosomes
The complex of DNA and protein found inside the nuclei of eukaryotic cells is called
Chromatin
5 classes of histones
H1, H2A, H2B, H3, and H4
5 classes of histones These small proteins are positively charged at physiologic pH as a result of their high content of
Lysine
Arginine
antibiotics target bacterial DNA gyrase
Quinolones
controlled by topoisomerases which later the topology of the circular DNA but not its covalent structure
Super coiling
relax DNA from negative supercoils formed
Type 1 topoisomerase
change DNA by creating double break strands in DNA
Type 2 topoisomerase
abundant proteins associated with eukaryotic DNA and are a family of basic proteins rich in the positvelycharged amino acids lysine and arginine which interact with the negative charges of DNA
Histones
RNA is a polymer composed of alternating units of
Ribonucleotides
RNA is a polymer composed of alternating units of ribonucleotides connected through a
3-5 phospodiesterase bond
Histones, along with positively charged ions such as _________ help neutralize the negatively charged DNA _____________
Magnesium
Phosphate group
HIV affects cells of the immune system, called
CD4 cells or T cells
most likely was transmitted to humans and mutated into HIV when humans hunted these chimpanzees for meat and came into contact with their infected blood
Simian Immunodeficiency Virus, or SIV from chimpanzees in west Africa
HIV family and subfamily?
Family Retroviridae-Subfamily Lentivirus
HIV 1
chimpanzees; pan troglodytes
HIV2
sootey mangabeys, more related to SIV 2
Retroviridaeis a single stranded RNA virus that has______________, which converts singlestranded RNA viral genome into doublestranded viral DNA
Reverse transcriptase
This new DNA is then incorporated into the host cell genome by an
Integrase enzyme
contains enhancer and promoter regions of HIV
LTR or long terminal repeat
encodes structural proteins which help in packaging RNA of the virus to generate new virus particles
Gag
encodes reverse transcriptase and integrase
Pol gene
codes for envelope proteins, along with the host plasma membrane complete the virus particle that buds off from the cell
Env
Regulatory proteins
Nef(negative factor), Tat(transactivator of transcription) and Rev (regulator of viral gene expressionresponsible for switching early to late HIV gene located in the 3’ end of envgene
catalyzes the insertion of viral DNA into the host genome to establish infection
Integrase
packaged in a capsidand buds out of the plasma membrane
Assembly and budding
Early stage–Within 2-4 weeks, many experience flu-like symptoms, often described as the “worst flu ever” also known as
Acute retroviral syndrome orprimary HIV infection
the first FDA-approved test that independently distinguishes results for HIV-1 p24 antigen and HIV antibodies in a single test
HIV-1/2 Ag/Ab
helpful in closing the window period (the time between HIV infection and appearance of antibodies to HIV
HIV antigen-antibody combination assay
People who are infected with HIV experience no HIV-related symptoms, or only mild ones
Asymptomatic HIV infection” or “Chronic HIV infection
Asymptomatic HIV infection” or “Chronic HIV infection
Clinical latency stage
Terminates elongation process–Zidovudine, didanosine, stavudine, lamivudine, abacavir–Prevent acute infection of susceptible cells
Nucleoside reverse transcriptase inhibitors
binds to the active site induces conformational change and inhibiting enzyme function–Delaviridine, nevirapine, efavirenz–Easily metabolized by cytoP450 system and prone to drug interaction
Non nucleoside inhibitor
inhibits HIV protease which activates precursors of gag-pol–binds to the active site of HIV protease and blocks viral maturation–Saquinavir, ritonavir, indinavir, nelfinavir–Side effects: nausea, vomiting, diarrhea
Protease inhibitor
2 Reverse transcriptase inhibitor, 1 protease inhibitor
HAART
Highly active antiretroviral therapy
12,241 cases, of which 93 percent—or 11,520—acquired the virus through sexual contact •85 % involved males having sex with other males (MSM) •Age group 15 to 24 was also notable in most new cases •11 patients with full-blown Aids at the time of reporting •Metro Manila accounted for more than half of the new cases (55%) while Calabarzonhad 14% •Other regions cited were: Central Visayas, 7%; Central Luzon, 3% and Davao region, 5
Nice to know
Timothy Brown also known as the “Berlin patient” •Diagnosed with HIV in 1995 •After controlling the virus for many years with antiretroviral therapy, Brown was diagnosed with acute myeloid leukemia (AML) and in 2007, destruction of his immune system and a stem cell transplantionwas done from a donor with a rare genetic mutation (homozygous CCR5∆32) that resists HIV infection •Nearly four years after his transplant, Brown remains free of both his cancer and readily detectable HIV
Nice to know
Lyme disease
spirocheteBorrelia burgdorferi
Three shape of spirochete
cocci(spheres)–bacilli(rods)–spirochetes(spirals
Weakly staining, gramnegative spirochetes largest medically important bacteria Stains well with aniline dyes (Giemsaor Wright
Borreliaburgdorferi
Borreliaburgdorferi curtured on
BarbourStoenner-Kelly medium
Transmission of lyme disease
bite from deer tick Ixodes scapularis
Once in the skin, the spirochete can:–Be eliminated by host defense mechanisms–Remain viable and localized in the skin where it
Erythema migrans
Characteristic expanding rash (target lesion) at the site of the tick bite 7-14 days after the tick is removed
Erythema migrans
Erythemamigrans is an example of
Erythema mutiforme
Dark center of small papule, vesicle, or bulla •Pale intermediate zone •Peripheral rim of erythema
Erythema mutiforme
Atrophy and skin as thin as cigarette paper
Acrodermatitischronicumatrophicans
Occurs within 30 days of Erythema migrans Fatigue, myalgias , bite arthralgias , headache, fever, chills, and neck stiffness
Early lyme disease
Occurrs weeks to months after the bite. Musculoskeletal and neurologic symptoms are the most common Cardiac and dermatologic
Early disseminated lyme disease
Months to years after infection Musculoskeletal (mainly joints) and neurologic systems are most commonly affected
Later or chronic lyme disease
A tetracycline drug that inhibits bacterial protein synthesis by binding to and interfering with ribosomes
Doxycycline
Cell wall inhibitors
Penicillin
Cephalosphorin
DNA synthesis inhibitors
Quinolones
Metabolic inhibitors
Folate inhibitor
50 + 30 = 70
Prokaryotic ribosomes
Protein synthesis inhibitor
Aminoglycosides Tetracylcines Macrolides Lincosamides Chlolamphenicol Linezolid
act on the ribosomesto inhibit translation
Protein synthesis inhibitor
Cell wall
Peptidoglycans
Unit
-10 to the minus 30
60+40=80
Eukaryotes ribosomes
bind to 30 s, preventing the binding of amiono acyl tRNAto heriosomes.
Tetracyclines
work against 30Ssub unit, stored the structure in iniation of protein synthesis stop.
- a suicide antibioticor bomb shell antibiotics, stop initiation of translation, incorporation of, prematurely termination of translation.
- example, gentamycin, streptomycin
Aminoglycosides
inhibit the formation of initiation complex of 30s and 50 s.
-last resort antibiotic, cause its very expensive
Linezolid
anti 50 S drugs, inhibits translocation
Macrolides
the most common, arise in epithelial cells
Carcinoma
from connective tissue (e.g. bone, cartilage
Sarcomas
from white blood cells
Lukemia and lymphomas
The sequence of events that occurs in the proliferation of individual cells is known as the
Cell cycle
which controls progression through the cycle so that, once the cell passes G1, it is committed to divide
G1
DNA is synthesized and the original DNA duplicated
S phase
the chromosomes separate and move to the two ends of the cell
G2
the cell divides to produce two daughter cells
M phase
the tissue contains cells that proliferate continually to replace those that die or are lost (e.g. the skin, intestine, bone marrow). These cells are known as stem cells
Continual renewing
the tissue contains cells (stem cells) that can be stimulated to proliferate in response to an appropriate signal (e.g. liver after injury, lymphocytes during an infection
Conditionally renewing
the cells in the tissue never proliferate (e.g. nerve, muscle) Most primary tumours arise in continually renewing tissues (often epithelium
Non renewing
TUMOR SUPPRESSION GENE
P 53
The protein p21 can be induced by p53independent factors, including drugs known as
Statins
Statins are used to lower blood cholesterol by inhibition of its synthesis, via the enzyme
HMG CoA reductase
sequences of six-nucleotide repeats found at the ends of the chromosomal DNA strands
Telomeres
These are present at the ends of the strands to overcome a problem posed by the semiconservative mechanism of DNA replication, known as
The end replication problem
present at the end of the 3′ strand
TTAGGG
at the end of the 5′ strand
AATCCC
Replication of the ends of the chromosomes presents particular difficulties, since DNA polymerase can only elongate a pre-existing DNA strand (it cannot initiate DNA synthesis) and can only polymerise DNA in one direction (5′ to 3
Need to know
Since there is no complementary strand from which to synthesise primers at the ends of the DNA molecule, up to 200 base pairs of DNA
Would be lost
Problem in cancer
no complementary strand
Tom maintain the length of the telomeres
enzyme, telomerase, which adds on repetitive nucleotides
In a normal cell, telomere length is gradually lost during cell replication and, when it is completely lost and then coding sequences are lost, the cell dies via
Apoptosis
Tumour cells, however, have an enhanced activity of telomerase which maintains the length of the telomeres which contributes to their
Evasion of normal apoptotic mechanism
compound that is foreign to the body
Xenobiotic
It may include drugs, chemical carcinogens, and various other compounds •The xenobiotic may be excreted unchanged, or it may me metabolized by the body’s enzymes to other compounds
Xenobiotic
2 phases of xenobiotic metabolism
- Hydroxylation / Biotransformation
2. Conjugation
Attachment of new functional groups,
Phase 1 biotransformation
Masking of an existing functional group
Conjugation
Catalyzed by cytochromeP450, a monooxygenase
Hydroxylation
Approximately 50% of the drugs humans ingest are metabolized by isoformsof
CYTOCHROME P 450
The reaction catalyzed by a monooxygenaseis as follows
RH + O2 +NADPH + H+→ R-OH + H2O + NADP
It is sometimes referred to as a Mixed Function Oxidase
Cytochrome P -450
Compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation
Conjugation
UDP-glucuronic acid is the glucuronyl donor, and glucuronosyltransferases
•This is the most frequent conjugation reaction
Glucuronidation
Sulfate donor is adenosine 3-phosphate5-phosphosulfate (PAPS), called “active sulfate
Sulfation
tripeptideconsisting of glutamicacid, cysteine, and glycine
Glutathione
are conjugated to the nucleophilic GSH: R+GSH→R—S—G
Electrophilic xenobiotic
R+GSH→R—S—G •The enzymes catalyzing these reactions are called
Glutathione S transferase
X+Acetyl-CoA→Acetyl-X + CoA •Catalyzed by__________ present in the cytosol of various tissues, particularly the liver
acetyltransferases
used in the treatment of tuberculosis, is subject to acetylation
Isoniazid
Polymorphic types of acetyltransferases exist, resulting in individuals who are classified as slow or fast acetylators •Slow acetylators are more subject to certain •toxic effects of isoniazid because the drug persists longer in these individuals
Acetylation
Xenobiotic may be converted from an inactive to a biologically active compound
prodrug or procarcinogen
conjugation may increase the biologic activity of a xenobiotic
Very few cases
it is the conjugation reactions that convert the active products of phase 1 reactions to less active or inactive species, which are subsequently excreted in the urine or bile
Other cases
PROPERTIES OF HUMAN CYTOCHROME P450
Hemoproteins
Broad substrate specificity
Liver and other tissues
Mitochondria or ER enzyme
Warfarin
Cytochrome
Phenobarbital
The preferred lipid in cytochrome P 450 is
phosphatidylcholine
