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M1 > BMS Midterm > Flashcards

BMS Midterm Flashcards

1
Q

Aminoacyl tRNA synthetase

A

Enzymes that catalyze aminoacylation (Addition of AA to the 3’ end of tRNA), can recognize anticodon on the 5’ end of tRNA, highly specific for one AA; need ATP to add AA; has an editing site for proofreading

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2
Q

Why is a ribosome more accurately called a ribozyme?

A

It catalyzes peptide bond formation and GTP hydrolysis without any other proteins

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3
Q

What happens during the initiation phase of translation?

A

(1) initiator tRNA +Met binds to small 40S rRNA subunit with eIF2 (needs GTP)
(2) tRNA/rRNA/eIF2 complex recognizes the eIF4E protein on 5’ mRNA cap (which is bound to eIF4G which bridges 5’ and 3’ mRNA ends)
(3) scan to find AUG codon (need ATP)
(4) large rRNA 60S subunit binds to pre-initiation complex –> GTP hydrolysis–> eIF2 leaves

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4
Q

What happens during the elongation phase of translation?

A

(1) eEF1A brings tRNA to A site, E site release
(2) GTP hydrolysis releases eEF1A and positions A site correctly (proofreading here)
(3) ribosome catalyzes peptide bond formation
(4) eEF2 + GTP bind to ribosome
(5) GTP hydrolysis releases eEF2 and moves protein from A site to P site

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5
Q

What happens during the termination phase of translation?

A

eRFI binds to A site when the stop codon comes up –> Catalyzes peptide hydrolysis

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6
Q

Proteins in translation initiation

A

eIF2 binds with initiator tRNA to small rRNA; eIF4E bound to 5’ mRNA cap; eIF4G bound to eIF4E and brings together 5’ and 3’ ends; helicase and ATP needed to scan for AUG start codon

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7
Q

Proteins in translation elongation

A

eEF1A brings tRNAs to A site; eEF2s act as translocases and move peptide to P site
*eEF1A also involved in protein degradation when chain doesn’t fold correctly

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8
Q

Proteins in translation termination

A

eRFI binds to A site at stop codon

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9
Q

Differences between translation from prokaryotes to eukaryotes

A

(1) happens simultaneously with transcription (no 5’ cap or poly A tail)
(2) polycistronic (one mRNA–> multiple genes)
(3) Shine-Delgarno sequence for initiation
(4) bacterial ribosomes smaller and different from eukaryotes enough for selective inhibition (for antibiotics, though side effects bc mitochondrial ribosomes are similar to bacterial)

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10
Q

Differences between translation from prokaryotes to eukaryotes

A

(1) happens simultaneously with transcription (no 5’ cap or poly A tail)
(2) polycistronic (one mRNA–> multiple genes)
(3) Shine-Delgarno sequence for initiation
(4) bacterial ribosomes smaller and different from eukaryotes enough for selective inhibition (for antibiotics, though side effects bc mitochondrial ribosomes are similar to bacterial)

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11
Q

What is miRNA? Why are they significant?

A

Micro RNA is short non-coding RNA that hybridizes to 3’ UTR end of mRNA –> forms RISC complex–> prevents ribosome from translating
*Mutations in miRNA cause many diseases e.g. Parkinsons

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12
Q

What is a RISC complex?

A

miRNA bound to 3’ UTR end of mRNA that prevents ribosome from translating

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13
Q

Does most translational regulation happen at 5’ end or 3’ end of mRNA?

A

3’ end, because you can make more subtle changes; any regulation at 5’ is ON/OFF switch

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14
Q

Explain iron homeostasis

A

(1) Low iron–> want to inhibit ferretin (which binds to iron)–> IRP (iron responsive protein) binds to 5’ UTR IRE (iron regulatory element)–> prevents pre-initation complex from forming–> inhibits translation of ferretin
(2) High iron–> IRP binds to iron to act as metabolic enzyme–> ferretin can be translated (example of 5’ UTR ON/OFF switch)

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15
Q

Explain nutritional status regulation of translation

A
  • In normal conditions: eIF2 used in first stage of translation to recruit initiator tRNA to 40S rRNA; eIF2B helps eIF2 go from GDP bound state to GTP bound state
  • In poor nutrition situations (e.g. low [AA], oxidative stress, immune response), eIF2 is phosphorylated and “stuck” to eIF2B, so it cannot be involved in translation–> translation is severely inhibited
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16
Q

Explain mTOR pathway

A

In hypoxia (low oxygen state), low mTOR activity–> eIF4EBP is dephosphorylated and binds to EIF4E and inhibits it, thereby inhibiting translation; in high growth, high mTOR activity–> eI4BP is phosphorylated and not bound to eIF4E and induces lots of translation and growth ( there is a ratio of bound to unbound eIF4E)

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17
Q

What are deiodinases?

A

Enzymes that contain selenocysteine, involved in activation of thyroid hormone

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18
Q

Explain selenocysteine incorporation

A

SEC-tRNA- only recognizes UGA and contains selenocysteine; eEFSec- brings SEC-tRNA to the A site; SECIS- marker on 3’ UTR mRNA for selenocysteine; SBP2- binds to SECIS and brings the whole SEC ternary complex to the mRNA UGA codon

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19
Q

What causes hypothyroidism?

A

Mutations in SBP2 gene needed for selenocysteine incorporation–> reduced selenocysteine–> reduced deiodenases –> decreased thyroid hormone production

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20
Q

What causes hypothyroidism?

A

Mutations in SBP2 gene needed for selenocysteine incorporation–> reduced selenocysteine–> reduced deiodenases –> decreased thyroid hormone production

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21
Q

How does polio virus work?

A

Poliovirus protease cleaves eIF4G; poliovirus binds and recruits initiation complex without needing 5’ cap
*efficient viral mRNA translation at the expense of host translation

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22
Q

How does diptheria toxin work?

A

It modifies the eEF2 translation factor and inactivates it–> inhibits translation in elongation stage

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23
Q

Protein folding theory: Linus Pauling

A

Secondary structure informs 3D tertiary structure (proposed alpha helices and beta sheets)

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24
Q

What are the three mutations that occur at the translational level?

A

Silent, nonsense, missense

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25
Q

Protein folding theory: Anfinsen

A

Native structure of protein is in its amino acid sequence (remove denaturant slowly and proteins regains almost full activity)

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26
Q

Protein folding theory: Levinthal

A

Only subset of possible conformations for folding–protein cant go through them all or it would take too long

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27
Q

Protein folding theory: Bryngelson and Wolynes

A

Principle of minimal frustration (side chains have evolved to max correct folding and min barriers)

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28
Q

What is GroEl chaperone

A

protein goes into large orifice and is twisted to try to fix misfolding–> need 14 ATP (chemical energy to mechanical torque)

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29
Q

How is proteasome assembled?

A

chaperone ump1 brings two rings of proteosome together and activates it (then ump1 is eaten up)

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30
Q

What is RING protein?

A

forms structure that can trap a metal atom e.g. Zinc

Zinc forms “zinc fingers” that bind DNA in zinc-finger transcription factors e.g. glucocorticoid

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31
Q

Cystic fibrosis transmembrane receptor protein mutation

A

Mutation in protein causes it to fold slowly- is captured by proteasome and degraded; small fraction is able to assemble correctly–> depletes intracellular levels of a critical transporter

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32
Q

What are the key features of a chaperone?

A
  • may or may not require ATP

- do not remain associated with target

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33
Q

Important determinants of protein folding

A

disulfide bonds and metal coordination (stabilizes), VdW interactions and electrostatic interactions (impacts local environment), hydrophobic core collapse (impacts global protein structure)
*lot of diseases caused by protein aggregation- Parkinson’s, Angelman’s, Huntington

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34
Q

Roles of chaperones

A

1) Protein synthesis (protect nascent chain, prevent kinetic dead ends, guidance but doesnt make it go faster)
2) Complex assembly of large proteins
3) Repairing misfolded proteins e.g. GroEl
4) Protein degredation/dissasembly (unfolded proteins have to be guided to proteasome otherwise they aggregate)
5) Secretion via the ER

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35
Q

Important determinants of protein folding

A

disulfide bonds and metal coordination (stabilizes), VdW interactions and electrostatic interactions (impacts local environment), hydrophobic core collapse (impacts global protein structure)

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36
Q

What are the three characteristics of ubiquitin?

A

1) Highly reactive carboxy terminus (from end Glycine residue)
2) lysine residues on surface
3) small hydrophobic patches on surface (4-8 for max effect)

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37
Q

What are the three characteristics of ubiquitin?

A

1) Highly reactive carboxy terminus
2) lysine residues on surface
3) small hydrophobic patches on surface

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38
Q

Combinatorial diversity

A

Combinations of E2 and E3 partnerships can destroy different substrates (800 E3 and 100 E2s can destroy thousands of different substrates)
*some E3 can form thioester bonds and others (e.g. RING proteins, cannot)

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39
Q

Combinatorial diversity

A

Combinations of E2 and E3 partnerships can destroy different substrates (800 E3 and 100 E2s can destroy thousands of different substrates)

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40
Q

Explain protein degradation pathway

A

1) Multi-Ub chain binds 19S particle
2) 6 ATPases unfold substrate and feed into alpha subunit orifice of 20S particle
3) Substrate hydrolyzed in interior of 20S
4) Ub recycled

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41
Q

Inflammatory/stress response pathway (involving proteasome)

A

1) Nfk transcription factor cleaved by protease into smaller parts, which are secluded in the cytosol by IKBalpha
2) In times of stress, kinase is activated through proteosome inhibitor degradation –> phosphorylates IKBalpha
3) IKBalpha is inhibited, so transcription factor goes into nucleus and activates transcription of stress-responsive genes, including lkBalpha

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42
Q

Inflammatory/stress response pathway (involving proteasome)

A

1) Transcription factor cleaved by protease into smaller parts, which are secluded in the cytosol by IKBalpha
2) In times of stress, kinase is activated through proteosome inhibitor degradation –> phosphorylates IKBalpha
3) IKBalpha is inhibited, so transcription factor goes into nucleus and activates transcription of stress-responsive genes, including lkBalpha

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43
Q

Types of epigenetic modifications and how they are incorporated in euchromatin?

A

1) DNA methylation- methylation of C stops transcription (also histone methylation)
* demethylated in euchromatin
2) Acetylation- unwinds the chromatin and opens it up to transcription factors
* acetylation in euchromatin
3) non-coding RNA- e.g. The Xist gene encodes a non-coding RNA which mediates X inactivation
* Xist inactivated by Tsix in euchromatin

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44
Q

Describe X inactivation

A

One X chromosome in the cell is randomly turned off by Xist

1) Xist coats the inactive X chromosome (Barr body)
2) Tsix is expressed in active X; Tsix is antisense to Xist and inhibits it, thereby activating the chromosome–> leads to mosaic distribution in heterozygotes

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45
Q

2 methods for detecting DNA methylation

A

1) Bisulfite used to convert unmethylated C–> U, can track the differences in capillary gel electrophoresis
2) Using methylation insensitive and sensitive isoschizomer restriction enzymes to cut and electrophorese
* methylation patterns change over time, even among identical twins!

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46
Q

2 methods for detecting DNA methylation

A

1) Bisulfite used to convert unmethylated C–> U, can track the differences in capillary gel electrophoresis
2) Using methylation insensitive and sensitive isoschizomer restriction enzymes to cut and electrophorese

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47
Q

System I thinking

A

Fast, uses generalizations, jumps to conclusions–> majority of our daily decisions

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48
Q

System II thinking

A

Rational, takes effort, causes fatigue–> when we have time to think, there is info available, large consequences of error

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49
Q

Define evidence based medicine

A

Conscientious, explicit, judicious use of current best evidence to make decisions about the care of individual patients

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50
Q

Prevalence

A

people with disease / total pop

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51
Q

Cumulative incidence

A

new cases / # people at risk in a certain time period

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52
Q

Incidence rate/incidence density

A

new cases / # person-years

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53
Q

Absolute risk difference

A

I exposed - I unexposed

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54
Q

Risk ratio/relative risk

A

I exposed / I unexposed

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55
Q

Methods of controlling confounders

A

1) Randomization
2) Restriction
3) Matching
4) Stratification
5) Multivariable adjustment

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56
Q

What three characteristics define abnormal?

A

1) Unusual
2) Treatment does more harm than good
3) Associated with disease or increased risk

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57
Q

Mismatch Repair (what it fixes, steps and proteins involved, associated disease) What happens when MMR is defective and how do you detect it?

A

1) Fixes replication errors (no damage)
2) Damage recognized by Mut, MSH2/6 (sub), MSH2/3 (insert/del) which bind to DNA
- Mut, MLH1/PMS2 incise as endonuclease on either side
- helicase + exonuclease
- DNA pol III, pol delta/epsilon + ligase
3) Lynch syndrome- mutations in MSH2 (ovarian/prostate), MSH6 (endometrial), MLH1 (colon)
4) Defective MMR leads to MSI and shorter microsatellite fragments –> diagnose Lynch through MSI PCR (MSI leads to inconsistencies b/w panels) or IH (if one of the partners is missing, they will both be absent from the staining)
* Muir Torre is like Lynch but with skin cancer, Turcot is CNS tumor

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58
Q

Mismatch Repair (what it fixes, steps and proteins involved, associated disease) What happens when MMR is defective and how do you detect it?

A

1) Fixes replication errors (no damage)
2) Damage recognized by Mut, MSH2/6 (sub), MSH2/3 (insert/del) which bind to DNA
- Mut, MLH1/PMS2 incise as endonuclease on either side
- helicase + exonuclease
- DNA pol III, pol delta/epsilon + ligase
3) Lynch syndrome- mutations in MSH2, MSH6, MLH1
4) Defective MMR leads to MSI and shorter microsatellite fragments –> diagnose Lynch through PCR or IH (if one of the partners is missing, they will both be absent from the staining)

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59
Q

Nucleotide Excision Repair (what it fixes, steps and proteins involved, associated disease)

A

1) Fixes DNA bulky adducts (result of radiation e.g. UV which creates thymine dimers, environmental exposure to carcinogens, oxidation, smoking/tobacco)
2) Global Genomic (GG-NER): XP recognizes, helicase + excinuclease, DNA pol I, delta/epsilon + ligase
-Transcription coupled (TC-NER): CSA/CSB proteins recognize, helicase + excinuclease, DNA pol I, delta/episilon + ligase
3) XP- mutation in XP proteins (photosensitivity, cancer risk)
Cockayne syndrome- mutation in CSA/CSB (neurological disorders)

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60
Q

Nucleotide Excision Repair (what it fixes, steps and proteins involved, associated disease)

A

1) Fixes DNA bulky adducts (result of radiation e.g. UV, environmental exposure to carcinogens, oxidation, smoking/tobacco)
2) Global Genomic (GG-NER): XP recognizes, helicase + excinuclease, DNA pol I, delta/epsilon + ligase
-Transcription coupled (TC-NER): CSA/CSB proteins recognize, helicase + excinuclease, DNA pol I, delta/episilon + ligase
3) XP- mutation in XP proteins (photosensitivity, cancer risk)
Cockayne syndrome- mutation in CSA/CSB (neurological disorders)

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61
Q

Double stranded break repair (what it fixes, steps and proteins involved, associated disease)

A

1) Fixes double strand breaks (ionizing radiation e.g. X-rays and UV, topo inhibitor e.g. quinolone, other drugs like bleomycin, oxidative damage)
2) Non-homologous: recognized by ATM, Ku (broken DNA sensor) binds to DNA ends to align, Artemis/FEN1 remove frayed ends, polymerase joins ends
- Homologous: recognized by ATM, RAD51 aligns (Regulated by BRCA1/2), Rad52 binds, polymerase joins ends
3) Ataxia telangiectasia in both- mutation in ATM kinase protein which manages DSBR
- Mutated BRCA1/2 leads to high chance of breast cancer in homologous
- Werner’s syndrome in non homologous

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62
Q

Double stranded break repair (what it fixes, steps and proteins involved, associated disease)

A

1) Fixes double strand breaks (ionizing radiation e.g. X-rays and UV, topo inhibitor e.g. quinolone, other drugs like bleomycin, oxidative damage)
2) Non-homologous: Ku (broken DNA sensor) binds to DNA ends to align, Artemis/FEN1 remove frayed ends, polymerase joins ends
- Homologous: recognized by ATM, RAD51 binds (Regulated by BRCA1/2), Rad52 aligns, polymerase joins ends
3) Ataxia telangiectasia in both- mutation in ATM kinase protein which manages DSBR
- Mutated BRCA1/2 leads to high chance of breast cancer in homologous
- Werner’s syndrome in non homologous

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63
Q

Explain mRNA splicing

A

1) snRNP U1 recognizes 5’ GU intron splice site
2) snRNP U2 recognizes 3’ AG intron splice site
3) recognize each other and bring everything together
4) transesterification reaction creates 2’ to 5’ intron lariat
5) second transesterification reaction joins the two exons

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64
Q

Steps for transcription in prokaryotes

A

1) Initiation- sigma unit of RNA polymerase binds to two promoters 35’ and 10’ upstream
* principal site for regulation of transcription
2) Elongation- RNAP leaves sigma at promoter and transcribes, adding nucleotides to 3’ end
3) Termination- RNAP leaves DNA template, depends on DNA encoded signals
- Rho independent- stem + loop + UUU as lock and key
- Rho dependent- Rho factor binds at specific RNA sequence and inactivates RNAP when it comes in contact

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65
Q

Regulation of prokaryotic transcription

A

1) When cell has low glucose (high cAMP) and high lactose:
- cAMP binds to CAP and then CAP binding site on the DNA sequence, and attracts RNAP to promoter
- lactose binds to lac I repressor and prevents it from binding to operator site and inhibiting RNAP
- lac operon is ON, transcription can happen, and eventually beta galactosidase is made
2) When cell has high glucose and low lactose:
- no cAMP to bind to CAP, CAP binding site is empty
- lac I repressor is bound as a dimer to the operator and sterically inhibits RNAP from binding

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66
Q

Steps for transcription in eukaryotes

A

1) Initiation- TBP of TFIID recognizes promoter and binds TATA box, other subunits bring RNA Pol II over, bind different promoters, act as helicase–> creates preinitiation complex
- GTFs position RNA Pol II at the promoter, RNA pol II starts transcription
2) Elongation- RNA pol II leaves transcription factors behind and moves along template strand
3) Termination- RNA pol II leaves (cleavage signal encoded in the DNA, where polyA tail is added to 3’)

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67
Q

Regulation of eukaryotic transcription

A

-Agonists/antagonists bind to steroid hormone receptors to activate/repress transcription
Components of steroid hormone receptor:
-ligand binding domain- binds hormone to activate receptor
-DNA binding domain- binds to enhancer sequence as a dimer –> confer specificity
-Activation domain- recruits coactivators which change nucleosome (histone + 2 turns DNA) to reveal promoter and kickstart transcription so RNA polymerase II can bind (either through covalent bonding to histone or to ATP-dependent motor)
*many have Zing finger domains

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68
Q

Regulation of eukaryotic transcription

A

-Agonists/antagonists bind to steroid hormone receptors to activate/repress transcription
Components of steroid hormone receptor:
-ligand binding domain- binds hormone to activate receptor
-DNA binding domain- binds to enhancer sequence as a dimer –> confer specificity
-Activation domain- recruits coactivators which change nucleosome to reveal promoter and kickstart transcription so RNA polymerase II can bind

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69
Q

Steps for DNA replication

A

1) Initiation
- DNAa/ORC melts A-T rich origin of replication
2) Separation
- Helicase unwinds
- Single stranded binding proteins keep the two strands apart
- topoisomerase II relieves positive supercoiling (DNA gyrase), topo I relieves negative supercoiling in the back
* topo inhibitors cause them to become DNA breaking agents
3) Synthesis
- Primase/Pol alpha puts down RNA primer
4) Chain elongation
- DNA polymerase III/DNA pol delta (lagging)/epsilon (leading) take over and synthesizes with dNTPs and PCNAs
5) Proofreading- polymerase also proofreads in 3’–> 5’ direction
6) DNA pol I/DNA pol delta (displaces primer)+FEN1 remove RNA primers and fill in gaps
- DNA pol I/delta also proofreads
7) ligase binds

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70
Q

Differences between DNA replication in prokaryotes and eukaryotes

A
  • One origin of replication (P) vs many (E)
  • Histones (E)- displaced then reformed during replication
  • Telomeres (E)- prevent loss of terminal info, protects end of chromosome from degradation or fusion
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71
Q 
How is 02 affinity in Hb regulated by allosteric modulators:
pH
NO
CO2
2,3 BPG
A
  • pH- lower pH decreases 02 affinity because it protonates His which leads to stronger His-Asp interaction and stabilizes T state (Bohr effect)
  • NO- increases 02 affinity, binds to Cys and acts as vasodilator to increase blood flow
  • C02 decreases 02 affinity- forms carbamate with Val (stabilized by Arg) in T state, in the lungs the carbamate is broken and C02 is released; C02 in blood forms carbonic acid which lowers pH and stabilizes T state
  • 2,3 BPG decreases 02 affinity by binding to T state cationic nest
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72
Q 
How is 02 affinity in Hb regulated by allosteric modulators:
pH
NO
CO2
2,3 BPG
A
  • pH- lower pH decreases 02 affinity because it protonates His which leads to stronger His-Asp interaction and stabilizes T state (Bohr effect)
  • NO- increases 02 affinity, binds to Cys and acts as vasodilator to increase blood flow
  • C02 decreases 02 affinity- forms carbamate with Val (stabilized by Arg) in T state, in the lungs the carbamate is broken and C02 is released; C02 in blood forms carbonic acid which lowers pH and stabilizes T state
  • 2,3 BPG decreases 02 affinity by binding to T state cationic nest
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73
Q

Describe quarternary structure of Hb

A

2 alpha and 2 beta globins, each with a heme; most interactions bw alpha and beta but there is a Lys-Arg-Asp salt bridge bw the 2 alphas

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74
Q

Describe differences in T and R states of Hb

A
  • T state- Fe2+ out of plane with heme ring (unfavorable for 02 binding)
  • R state- Fe2+ in plane with heme and 02 binds, allostery induces changes in the other subunits to the R state –> basis of cooperativity
75
Q

How does HbF have a higher affinity for 02?

A

His in the cationic nest is replaced with a polar Ser–makes 2,3 BPG binding less favorable and overall T state conformation less favorable–> increases affinity for 02
–> 02 binding curve for HbF is shifted LEFT (higher 02 affinity, lower p50)

76
Q

Explain hemoglobinopathies (cause, symptoms, treatment):
HbS
HbC

A

1) HbS: B6Glu–> Val substitution creates hydrophobic pockets on Hb that cause them to clump together, sickles the RBC and they aggregate reducing blood flow + 02
- causes painful sickle cell crises esp in deoxy T state where there are more hydrophobic patches and they are way less soluble which causes sickling
- treatment: transfusion (+ iron chelators), penicillin, hydroxyurea, bone marrow transplant
2) HbC: B6Glu–> Lys substitution causes the Hb to crystallize in RBCs- reduces deformity in RBCs
- mild hemolytic disorder, milder symptoms than HbS
- you do see Hb SC (heterozygotes for Bc and Bs mutations)

77
Q

Explain thalassemias (cause, symptoms, treatment)
alpha
beta

A

1) Alpha thalassemia: deletions in any of the 4 alleles for alpha globin
- Normal (4 alpha genes)
- Silent carrier (3 genes)
- Alpha thalassemia trait (2 genes)- hypochromic, microcytic anemia
- HbH (1 gene)- unstable B4 tetramers which precipitate as Heinz bodies, leads to moderately severe anemia, mild jaundice
- HbBarts (0 genes)- gamma4 tetramers, hydrops fetalis fetal death

2) Beta thalassemia: substitutions in any of the 2 alleles for beta globin
- thalassemia minor (1 affected allele)- carrier, slightly anemic but otherwise asymptomatic, increase in HbA2 and HbF
- thalassemia major (2 affected alleles)- severe anemia, need lifelong management
* caused by RNA splicing errors e.g. intron 3’ AG site moves upstream and leads to longer exon

3) Treatment:
- blood transfusion + iron chelators
- bone marrow transplant

78
Q

Explain thalassemias (cause, symptoms, treatment)
alpha
beta

A

1) Alpha thalassemia: deletions in any of the 4 alleles for alpha globin
- Normal (4 alpha genes)
- Silent carrier (3 genes)
- Alpha thalassemia trait (2 genes)- hypochromic, microcytic anemia
- HbH (1 gene)- unstable B4 tetramers which precipitate as Heinz bodies, leads to moderately severe anemia, mild jaundice
- HbBarts (0 genes)- gamma4 tetramers, hydrops fetalis fetal death

2) Beta thalassemia: substitutions in any of the 2 alleles for beta globin
- thalassemia minor (1 affected allele)- carrier, slightly anemic but otherwise asymptomatic, increase in HbA2 and HbF
- thalassemia major (2 affected alleles)- severe anemia, need lifelong management

3) Treatment:
- blood transfusion + iron chelators
- bone marrow transplant

79
Q

What are the main TFII factors in eukaryotic transcription

A
  • TFIID- tells RNA pol II where to bind (TBP subunit binds to TATA box)
  • TFIID- promoter recognition
  • TFIIH- helicase which melts dsDNA
  • GTFs- align RNA pol II over core promoter (like sigma subunit in prokaryotes)
80
Q

Explain mRNA processing

A

After transcription need to make mature mRNA:

  • 5’ cap added (5’ to 5’ linkage)–> not encoded in DNA, helps with start of translation
  • 3’ polyA tail added –>not encoded in DNA, protects mRNA
  • introns spliced out–> 5’ GU and 3’ AG, 2 transesterification reactions
81
Q

Do substrates bind better in organic solvents or water?

A

Organic solvents because water competes with the electrostatic interactions that take place between enzyme + substrate

82
Q

Types of catalytic strategies and who uses them:

  • proximity
  • transition state stabilization
  • covalent catalysis
  • acid base catalysis
  • oxyanion hole
A
  • proximity- all enzymes
  • TS stabilization- all enzymes
  • covalent catalysis- forming covalent bond with substrate and Serine, need a nucleophilic (e- rich) enzyme–> Serine O-
  • acid base catalysis- His acts as both acid and base (favorable bc pKa =6), Asp raises His pKa so it can act as a base
  • oxyanion hole- stabilizes negative 0- on tetrahedral intermediate
  • -> chymotrypsin uses all 3 strategies in its catalytic triad: Ser, His, Asp to increase rate of peptide hydrolysis
83
Q

Which amino acid is most commonly phosphorylated? Then which two?

A

Serine, then threonine, then tyrosine (all polar with OH)

84
Q

Allosteric inhibitors:
K-type
V-type

A

Allosteric inhibitors show sigmoidal binding (eg Hb)
K-type: like a competitive inhibitor–> increases K0.5, does not affect Vmax
V-type: like a noncompetitive inhibitor–> no change in K0.5, reduces Vmax (Activity of E lower for all [S])

85
Q

Allosteric activators:
K-type
V-type

A

K-type: decrease K0.5, does not affect Vmax (Activity of E higher for low [S] , then levels out since Vmax is the same)
V-type: does not affect K0.5, increases Vmax (Activity of E higher for all [S])

86
Q

2 ways to determine 3D structure of proteins

A

1) NMR spectroscopy
2) X-ray crystallography
* Structure is NOT used for de novo drug design

87
Q

Difference between globular and fibrous proteins

A

Globular–function (spherical, large in number)

Fibrous–structure (elongated, small in number but large in mass)

88
Q

Which AA are known as helix breakers and where are they commonly found?

A

Gly and Pro- found commonly in tight turns on surface of proteins

89
Q

Which AA are known as helix breakers and where are they commonly found?

A

Gly and Pro- found commonly in tight turns on surface of proteins

90
Q

What is the significance of phy and psi angles?

A

Two allowable conformations- repetition of one is alpha helices and of the other is beta sheets
combo of both is turns and loops

91
Q

Which three AA can be glycosylated?

A

Serine, Threonine, Asparagine

92
Q

Three features of the peptide bond

A

Planar, polar, trans

93
Q

Forces that stabilize protein tertiary structure

A

Ionic interactions, disulfide bridges, VdW interactions, hydrophobic interactions, H-bonds

94
Q

Two major classes of proteins that contain heme prosthetic groups, and the role of heme

A

1) Cytochrome p450 in the liver and hemoglobin (blood)/myoglobin (muscle)
2) heme is prosthetic group and binds to the 02

95
Q

Major organs with highest rate of heme biosynthesis

A

1) Liver (for cytochrome p450 enzymes)

2) erythropoetic cells (immature RBCs)

96
Q

Special feature of porphyrins?

A

Oxidized form of porphyrinogens, oxidized has extended conjugated system and can absorb visible light
releasing this energy creates oxygen radicals

97
Q

Describe second step of heme biosynthesis

  • where it takes place
  • substrates, product, enzyme
A

1) takes place in cytoplasm
2) Substrates- 2 ALA condense
Product- PBG
Enzyme- ALAD, includes bound Zn++ cation (inhibited by lead, bc Pb can replace Zn++)

98
Q

Describe second step of heme biosynthesis

  • where it takes place
  • substrates, product, enzyme
A

1) takes place in cytoplasm
2) Substrates- 2 ALA condense
Product- PBG
Enzyme- ALAD, includes bound Zn++ cation (inhibited by lead, bc Pb can replace Zn++)

99
Q

Describe last step of heme biosynthesis

  • where it takes place
  • substrates, product, enzyme
A

1) takes place in mitochondria
2) Substrate- Protoporphyrin IX + Fe 2+
Product- Fe-Protoporphyrin IX
Enzyme- Ferrochelatase (inhibited by lead because Pb can also replace Fe2+)

100
Q

Lead poisoning:

  • enzymes inhibited by lead
  • potential exposures to lead
  • clinical presentation of lead poisoning
  • diagnosis of poisoning
  • treatments available
A

1) ALAD and Ferrochelatase inhibited by lead (ALAD more sensitive)
2) Exposures: construction, painting, repair, plumbing
3) clinical presentation- long bone lead line, anemia, cramps, arthralgia
4) Diagnosis- accumulation of ALA, basophilic stippling (purple pic), zinc protoporphyrin (zinc replaces Fe)
5) Treatment- lead chelators

101
Q

Acute intermittent porphyria (AIP):

  • cause
  • mode of inheritance
  • accumulating molecules
  • symptoms
  • detection
  • treatment
A

1) Cause- mutation in PBGD (PBG–> HMB)
(2) Mode of inheritance- autosomal dominant
3) Accumulation of PBG and ALA
4) Symptoms- no skin lesions, but neurotoxic (psych disorders, paralysis), onset at puberty
5) Detection- brown urine bc of PBG oxidizing
6) Treatment- Hemin (inhibits ALAS by feedback inhibition), Avoid 4Ms (inhibits ALAS1 transcription), glucose loading (increased glucose inhibits ALAS1 synthesis)

102
Q

Porphyria cutanea tarda (PCT):

  • cause
  • mode of inheritance
  • accumulating molecules
  • symptoms
  • detection
  • treatment
A

1) Cause- mutation in UROD (UroIII–> Copro III)
- also caused by alcohol, sun exposure, Hep B C or HIV, hepatic iron overload
2) Acquired, autosomal dominant- most common and treatable
3) Accumulation of UroIII (Uroporphyrinogen)
4) Symptoms- skin lesions, facial hair growth, white bumps, photosensitivity, onset in 40/50s
5) Detection- coral urine fluorescence
6) Treatment- sunscreen, iron chelation, phlebotomy, remove environmental exposures, avoid 4Ms

103
Q

Erythropoietic protoporphyria (EPP):

  • cause
  • mode of inheritance
  • accumulating molecules
  • symptoms
  • detection
  • treatment
A

1) Cause- mutation in ferrochelatase
2) autosomal dominant
3) Accumulation of iron, Protoporphyrin IX
4) Symptoms- extreme photosensitivity, onset in childhood
5) Detection- fecal analysis
6) Treatment- sunscreen and avoid sunlight

104
Q

Sideroblastic anemia:

  • cause
  • mode of inheritance
  • accumulating molecules
  • symptoms
  • detection
  • treatment
A

1) Many causes including: ALAS2 mutation, lead, Vitamin B6 deficiency, drugs (isoniazid, ethanol)
2) can be inherited (X-linked) or acquired
3) Accumulation of succinyl co-A, glycine, vitamin B6
4) Symptoms- hypochromic, microcytic anemia
5) Detection- ring sideroblasts in bone marrow, acc of iron in mitochondria
6) Treatment- lead chelators, transfusion

105
Q

What is an operator?

A

Segment of DNA to which a transcription factor (i.e. repressor) binds to regulate gene expression through the promoter
-classic example is the lac operon (in prokaryotes only!)

106
Q

What is the relationship bw prevalence and incidence?

A

Prevalence = Incidence x duration

107
Q

What do overlapping confidence intervals signify? What about non overlapping CI?

A

Overlap- Implies the difference is not significant

If CI do not overlap–there is a significant difference (you can be 95% confident of it)

108
Q

What is a cross-sectional study? What are the pros and cons?

A

Measure exposure and disease simultaneously– snapshot to look at prevalence

  • Pros: quicker, cheaper (no follow up), representative of overall pop
  • Cons: Don’t know direction of association
109
Q

How do you calculate relative risk for a cohort study?

A

(Cases/total exposed)/
(Cases/total unexposed) OR
[A/(A+B)]/[C/(C+D)] when looking at 2x2

110
Q

What is a cohort study? What are the pros and cons?

A

Cohort that doesn’t have but is at risk of disease is grouped by exposure –> outcomes; can be retrospective or prospective depending on when cohort was assembled

  • Pros: Good when exposure is rare, minimizes selection/measurement bias, can look at multiple outcomes from single exposure, can directly determine incidence rate/risk
  • Cons: Expensive, requires large N, takes long time, not good for rare diseases
111
Q

What is a case cohort study?

A

All incident cases are compared to a random sample or subset of controls
-type of nested cohort study

112
Q

How do you control selection bias and measurement bias in a cohort study?

A

Selection bias– make sure exposed/unexposed groups are representative samples from same population (identical except for exposure)
-healthy worker effect bias
-lost to follow up bias
Measurement bias- blind interviewers to exposure status when looking at outcomes

113
Q

Which type of study would you use to measure prevalence?

A

Cross-sectional study

114
Q

Which type of study would you use to measure risk of harm?

A

Cohort, then case-control

115
Q

Which type of study would you use to measure treatment or prevention?

A

Randomized control trial, then cohort, then case-control

116
Q

Which type of study would you use to measure prognosis (course of a disease)?

A

Cohort

117
Q

Which type of study would you use to measure screening?

A

RCT, then cohort, then case-control

118
Q

What is a case-control study? What are the pros and cons?

A

ID if exposure is related to outcome by having cases and controls and looking at their exposures –> one of first approaches when studying disease etiology and can suggest hypotheses to test in add’l studies

  • Pros: good for rare outcomes/diseases, diseases with long induction period e.g. cancer, exploring multiple exposures, inexpensive + faster, good for dynamic populations
  • Cons: lots of possible types of biases esp. exposure misclassification and recall, can’t measure incidence directly, restricted to single outcome, tough if frequency of exposure is low
119
Q

What are the biases for case control studies? How do you minimize them?

A

Selection bias: could be over or under sampling –> avoid overmatching
-big problem is selecting controls in a way related to exposure –> controls should be selected independent of exposure
-also diagnostic bias (case selection influenced by physician knowledge of exposure)
-cases and controls should be identical except for outcome, both from source population
Measurement bias:
-Exposure misclassification- can be differential (bias to Type I/II) or nondifferential (bias towards null)
-also recall bias (case might remember better than control)–> use records of exposure prior to disease or verify with another source, choose recent cases, blind subjects
-precise case and exposure definitions
-also investigator bias–> blind interviewers to whether subject is case or control

120
Q

How do you calculate the odds ratio for a case-control study? When is it similar to the risk ratio in a cohort study?

A

Odds of exposure in cases / odds of exposure in controls OR
(A x D) / (B x C) when looking at 2 x 2
-similar to risk ratio when the incidence rate is low

121
Q

What is a nested case control study?

A

Selects cases and controls from within a cohort study

-get add’l info on exposures from just cases and controls

122
Q

What is non-differential misclassification? Differential misclassification?

A
  • Non-differential: misclassification occurs in same prop in each group, biases towards null/type II error
  • Differential: cases report exposure differently than control, can bias towards or away from association (type I or II error)
123
Q

What type of study would you use in an outbreak investigation?

A

Case-control study

124
Q

What is the source population for a case-control study?

A

The population that generated the cases
-Make sure controls are a representative sample of the exposure status of the source population
(Ask “if the control had the disease, would they have been enrolled as a case?”)

125
Q

Methods for selecting controls

A
  • population based case control study (best approach)- cases come from a specific population, and controls are sampled randomly from the same pop e.g. directory, voter registration list
  • hospital control- cases and controls from same facility
  • ->minimizes selection and recall bias and more likely to participate, but controls must have different diagnosis and similar referral pattern
  • other population sources- neighbors, friends, family (controls for potential confounders)
126
Q

What is the difference between parametric and non-parametric tests? Which is susceptible to outliers?

A

Parametric- variables are normally distributed
-r and r squared
-continuous variables
-susceptible to outliers
Non-parametric- based on rank, not actual values
-spearman rho (rs) and kentall tau

127
Q

What is the main use of multivariate regression? (aka multiple logistic regression)

A

Adjust for confounders by determining individual contribution of each variable

  • gives direct estimate of the odds ratio for each independent variable
  • dependent variable is binary (e.g. disease or not)
128
Q

What is the main use of principal component analysis?

A

Reduces lots of variables and makes it graphable in 2 or 3 dimensions

129
Q

What are Kaplan Meier curves?

A

Survival analysis curves e.g. 5 year survival –> most widely used (but not only method)

  • horizontal is time period
  • vertical drop is event/dropout
  • can compare survival curves in 2+ groups
  • get a smooth curve for large N
  • Con–> cannot handle covariates (effect of risk factors on survival)
130
Q

Define equipoise

A

Lack of consensus in the medical community about a treatment or prognosis
-then you can have RCT OR let patients choose

131
Q

What is a Cox regression/Cox proportional hazards?

A

Multivariate survival analysis, often used with Kaplan-Meier

  • can adjust or control for other factors
  • flexible to lost to follow up
  • calculates hazard ratio, same concept as RR or odds ratio (1=2 groups have same survival, 1.25–> risk carries 25% increased chance of death)
132
Q

When is a study internally valid?

A

When you have ruled out random error, bias, and confounding

133
Q

What are the two main types of bias?

A
  • Selection bias- samples are not representative of population
  • Information bias- arises from errors in measuring exposure or disease
134
Q

Positive and negative predictive values- definition and equations

A

Positive predictive values- probability that someone who tests positive for disease actually has disease
=TP/(TP+FP)
Negative predictive value- probability that someone who tests negative for disease actually does NOT have it
=TN/(TN+FN)

135
Q

What is post test probability?

A

PV+ and PV- –> probability of disease after test has been given

136
Q

What is pre test probability and how does it affect post-test probability?

A

Prevalence–> probability of disease before test
low prevalence decreases positive predictive value regardless of Sn/Sp; prevalence of almost 100% decreases negative predictive value

137
Q

What is a likelihood ratio and what is the relationship w/ pre and posttest prob?

A

Likelihood ratio is the likelihood of a test result in diseased versus nondiseased groups
prettest * likelihood = posttest

138
Q

What is parallel testing? What is serial testing? How is diagnosis made in each?

A

Parallel testing- any test needs to be positive for disease diagnosis (when you need rapid assessment)
–> increases sensitivity and negative predictive value (will have false positives)
Serial testing– all tests need to be positive for disease diagnosis (when tests are more expensive)
–> increases specificity and positive predictive value

139
Q

How do you calculate positive likelihood ratio? negative likelihood ratio?

A 
LR+ = Sens / (1-Spec)
LR- = (1-Sens) / Spec
140
Q

What biases occur when comparing index diagnostic tests to new ones?

A
  • Spectrum bias- patients not the same as in usual practice
  • Verification bias- not everyone gets both the reference and index/golden standard test
  • Observer bias- investigators know the result of the index test when doing reference test
  • Chance
141
Q

What is Central Limit Theorem?

A

The means (xbar) of random samples repeated many times will be normally distributed and estimate the true population mean (mu)

142
Q

What is alpha? What is beta? What is the power?

A

alpha- willingness to make Type I error
beta- willingness to make Type II error
power= 1-B, probability you will find a statistically significant difference when it really exists

143
Q

How do you calculate and interpret confidence intervals?

A

CI= Mean +/- (1.96 * SEM) where SEM=SD/sqrt(N)

We are 95% confident that the true value lies within the confidence interval

144
Q

What does it mean if confidence intervals contain 0?

A

Not significant if you are looking at regression/difference

For relative risk, odds ratio, and hazard ratio–> the important number is 1!

145
Q

What is the danger of looking at multiple variables when doing a regression?

A

With multiple, there is a greater chance that at least one of them will be statistically significant due to chance alone (type I error)

146
Q

What is cross-over? What is co-intervention? How do they affect study results?

A

Cross-over- patient moves from one treatment to the other
-biases towards null (lowers effect size)
Co-intervention- patient is given another drug or intervention during the trial
-can either decrease or increase the effect size

147
Q

What are the four levels of blinding in an RCT and what biases can result?

A 
1- treatment allocation 
results in selection bias in failure to conceal the allocation
2-patients
3-clinicians
4- investigators who measure outcome
2, 3, 4 result in measurement bias
148
Q

For a randomized control trial, define:

  • absolute risk
  • relative risk
  • relative risk reduction
  • absolute risk difference/attributable risk
  • NNT (#needed to treat)
A

Absolute risk = event rate
Relative risk = treated event rate / control event rate
Relative risk reduction = 1 - relative risk
Attributable risk/absolute risk reduction = Control event rate - treated event rate
NNT = 1 / absolute risk reduction (# people you treat before someone sees a benefit)

149
Q

What is the difference between efficacy and effectiveness? How does this relate to intention to treat vs explanatory analysis?

A

Efficacy- can treatment work under ideal circumstances?
-doesnt matter ITT or explanatory
Effectiveness- can treatment work under ordinary circumstances?
-use explanatory analysis

*Intention to treat- analyze results acc to the group the patient was assigned
-use this to preserve original randomization–> answers “which treatment choice is best?”
Explanatory analysis- analyze acc to the group that patient was actually in
-answers “does actually taking the treatment lead to better outcomes?”

150
Q

What is random error? What is systematic error? Are they differential and what error are they associated with?

A

Random error is due to chance, is nondifferential–> chance is associated with Type II error

Systematic error is due to bias, can be nondifferential or differential–> bias is associated with Type I

151
Q

What is a t test? What is a mann whitney test?

A

t-test compares the difference between two means (parametric)
-if calculated t > set t (based on df and alpha)–> reject H0
Mann whitney test compares the difference in ranks (non-parametric)

152
Q

What is a randomized control trial? What are the pros and cons?

A 
RCT recruits patients using exclusive criteria and randomly assigns to treatment or control groups and analyzes the effect *need equipoise
Pros: 
-gold standard
-minimizes bias- groups same except for treatment
-maximizes internal validity
Cons: 
-minimizes generalizability
-long and expensive, not always feasible
-bias still exists
153
Q

What bias exists in RCTs?

A

Failure of randomization:
-lost to follow up
-misconcealed/failure to conceal allocation
-co-intervention
-cross-overs
Measurement bias- differential, when blinding isnt good enough

154
Q

Explain the types of prevention

A

Primary- before exposure by removing causes
-e.g. sanitation, nutrition, immunization (–> Risk)
Secondary- after disease is there but asymptomatic
-e.g. early detection/screening (pap smear), early intervention (–>Prognosis)
Tertiary- disease is clinically recognizable, prevent complications/reoccurrence
-e.g. treatment, rehabilitation

155
Q

Explain the four types of clinical prevention

A

Behavioral counseling
Immunization
Screening
Chemoprevention- using drugs and diet

156
Q

Explain the following biases that make screening look good:

  • lead time bias
  • length time bias
  • compliance bias
A

Lead time bias- Earlier detection of the disease but no benefit/no effective treatment –> appears to increase survival time but its not true
Length time bias- screening more likely to pick up slower growing diseases with better prognosis (ones who die go to doctor with symptoms and are not screened)–> appears to be protective but its not
Compliance bias-people who get screened are more likely to have other healthy habits and have better prognosis regardless of screening

157
Q

When can screening be bad?

A

Overdiagnosis- early diagnosis of a tumor that would not have caused any problems

  • can lead to costly, unnecessary treatment and complications
  • quarternary prevention- avoid overdiagnosis
158
Q

What are the WHO guidelines for a good screening program?

A
  1. important health problem (serious, preventable, high prevalence)
  2. accepted treatment
  3. treatment access/affordability
  4. latent stage with biomarker that can be detected (otherwise what is the point of screening?)
  5. good test–> sensitivity, specificity, positive predictive value
  6. acceptable test- short turnaround time
  7. know the natural history of the disease
  8. policy set for how to treat
  9. cost effective
  10. screening in for the long haul (e.g. TB- came back as MDR TB)
159
Q

What are Koch’s postulates?

A

Every disease has one cause and one cause results in one disease

  • organism must be present in every case
  • must be isolated and grown in culture
  • should cause disease when introduced
  • must be reisolated from newly infected host
160
Q

What is necessary? What is sufficient? Where does infectious disease e.g. HIV/AIDS fall?

A

Necessary- will not happen without this factor
Sufficient- this factor is all you need
HIV is necessary but not sufficient- need cofactors eg. poor nutrition, TB exposure

161
Q

What is required before deciding causal pathway is likely?

A

Rule out bias, confounding, and chance

162
Q

What is an ecological study? Ecological fallacy?

A

Ecological study- looks at groups rather than individuals
fallacy- don’t know if individuals with the outcomes are the ones who were exposed to the risk
*good for raising hypotheses

163
Q

What are the two studies that illustrate the impact of the environment on epigenetics?

A

Environmental changes on phenotype can affect epigenetic changes on gene function

1) Hongerwinter- children born years later to people who survived Dutch famine had same IGF2 methylation and were stunted
2) Agouti mice- methylated Agouti gene leads to brown healthy mice, unmethylated leads to yellow obese mice
- but if you give diet supplements in yellow mice–> in 3 generations back to brown mice
* btw mice are genetically identical

164
Q

What are the two studies that illustrate the impact of the environment on epigenetics?

A

Environmental changes on phenotype can affect epigenetic changes on gene function

1) Hongerwinter- children born years later to people who survived Dutch famine had same IGF2 methylation and were stunted
2) Agouti mice- methylated Agouti gene leads to brown healthy mice, unmethylated leads to yellow obese mice
- but if you give diet supplements in yellow mice–> in 3 generations back to brown mice
* btw mice are genetically identical

165
Q

What are two examples of nucleoside analogs?

A

1) AZT for HIV

2) Acyclovir for Herpes Simplex Virus (HSV)

166
Q

What is Rett syndrome- cause, inheritance, symptoms?

A

1) Cause- Mutation in MeCP2 (Methyl CpG binding protein)– the gene binds to CpG island in nerve cells and represses transcription; mutation causes transcription of these genes
2) Inheritance- X linked dominant (mostly girls)
3) Symptoms- apraxia, repetitive movements + seizures

167
Q

What is Rett syndrome- cause, inheritance, symptoms?

A

1) Cause- Mutation in MeCP2 (Methyl CpG binding protein)– the gene binds to CpG island in nerve cells and represses transcription; mutation causes transcription of these genes
2) Inheritance- X linked dominant (mostly girls)
3) Symptoms- mental retardation, repetitive movements + seizures

168
Q

What are the three principles for the Belmont report?

A

1) Beneficence- do no harm, max benefits and min harms
2) Respect for persons- informed consent
3) Justice- fair subject selection

169
Q

3 main groups of vulnerable patients in IRB studies

A

1) Prisoners
2) Pregnant women
3) children
* publicly available data does not need IRB approval

170
Q

How does diptheria toxin work?

A

It modifies the eEF2 translation factor and inactivates it–> inhibits translation in elongation stage

171
Q

What are the three molten globule formation models?

A

1) Hierarchical- independent secondary structures –> tertiary structure
2) Nucleation- one area forms quickly and promotes folding
3) Hydrophobic collapse- tertiary hydrophobic interactions
* proteins use combos of all three

172
Q

What is the significance of mature insulin structure?

A

Two separate polypeptide fragments held together by disulfide bonds– needs to be in oxidizing environment

173
Q

What are agents/conditions that promote protein unfolding?

A

1) temperature
2) pH
3) pressure
4) urea
5) guanadine (strong base)
6) organic solvents

174
Q

What is unique about Ub/proteasome in terms of disease?

A

Cannot have mutations in either–> they are essential for life
Mutations are in the 1000+ regulatory proteins involved in getting substrate degraded (without proper degradation–> proteins aggregate and cause diseases)

175
Q

What is an immune-proteasome?

A

Expressed in immune cells to facilitate antigen presentation- displays cleaved antigens
Structure is slightly different from normal protease (the 3 active B subunits swapped out)

176
Q

What is phenotype plasticity?

A

Ability of one genotype to produce more than one phenotype when exposed to different environments

  • epigenetic changes due to environmental factors e.g. diet, stress
  • adult changes in neural pathways due to mood disorders, addiction
177
Q

What drug inhibits bacterial RNA polymerase?

A

Rifampicin (why we went through all the trouble of ID-ing the structure of RNAP)

178
Q

What are examples of core promoter elements? Proximal promoters?

A

1) Core- Pribnow box (-10), 35 upstream (-35) –>prokaryotes; TATA box (-25), DPE (+30), INR (+1)–> eukaryotes
2) Proximal- CpG islands (eukaryotes)

179
Q

Describe major features of the enzyme active site

A
  • small pocket with a few catalytic AA
  • nonpolar and excludes water- enhances substrate binding by increasing electrostatic interactions
  • binds susbtrates with weak noncovalent interactions e.g H bonds, electrostatic, hydrophobic, VdW
180
Q

What is the induced fit model?

A

Specific substrate induces conformational changes in the enzyme

  • molds to ideal transition state binding
  • excludes H20
  • orients catalytic groups
181
Q

What are the 4 hallmarks of enzymes? What do enzymes NOT do?

A

1) Catalyst - accelerates rxn w/out getting used up
2) Specific- induced fit model w/ tight binding to TS
3) Rate acceleration- increase the rate of reaction by decreasing the G for the transition state- NOT the G/free energy for the overall rxn
4) Can be regulated - temp, pH
* Enzymes do NOT change the free energy G for the reaction nor the equilibrium constant K, they do lower the G for the transition state to increase the rate of the reaction

182
Q

In what types of enzymes is pH optimum low and Vmax high? (when the rate limiting step is release of a substrate e.g. NADH)

A

Enzymes with neutral/uncharged side chains
-Enzymes with charged side chains e.g. Arg (pKa=12) need higher pH optimum to break the interactions, so and will have a lower Vmax

183
Q

What happens to free energy G during a spontaneous change?

A

Exergonic reaction- free energy G decreases and stability increases

184
Q

What affects Kcat and Km?

A

They are constants for a given enzyme/substrate, affected by pH and temperature
Kcat maxed when all enzyme bound to substrate

M1 (13 decks)

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