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Biochemistry I > Midterm 2 > Flashcards

Midterm 2 Flashcards

1
Q

5 Major Function Protein Classes

A

Metabolism, Structure, Transport, Cell Signaling, and Genomic Caretakers

(not totally inclusive and some fit into more than one group)

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2
Q

What are Metabolic Enzymes?

A

reaction catalyst that control metabolic flux

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3
Q

Facts about metabolic enzymes

A

●increases rate of product formation by lowering activation energy
●DOES NOT CHANGE DELTA G
●Responsible for the synthesis and degradation of macromolecules
●Amino acid side chains specify shape and chemical environment of enzyme active site (helps lower activation)
●most are part of multisubunit protein complexes (quarternary)
●names based on reactant and describe mechanism of reaction

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4
Q

What are Structual Proteins?

A

Most abundant proteins in living organisms and they function as architectural framework for individual cells, tissues, and organs

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5
Q

Structural protein facts

A

●Remember collagen
●maintain integrity of cell structures and promote changes in cell shape
●Cytoskeleton protein: responsible for cell shape, cell migration, and cell signaling

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6
Q

Examples of Cytoskeleton Proteins

A

Actin, Tubulin, and Collagen

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7
Q

Actin

A

●Abundant cytoskeletal protein in animal cells
●Found in muscles
● subunits self assemble from actin monomers to polymers called thin filaments

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8
Q

Function of thin filaments

A

●molecular cables controlling cell shape and cell migration
●also used in muscle contraction

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9
Q

Tubulin

A

●in animal cells
● self assemble from tubulin monomers to long polymers called microtubules

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10
Q

Function of microtubules

A

●act as “road” for movement of organelles and chromosomes during cell division
●pushes them together and pulls them apart (Mitotic checkpoint)

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11
Q

Collagen

A

●fibrous protein
●3 intertwines left-hand helices
●repeating Gly-Pro-4HyP tripeptide
●left handed helix with 3AA/turn
●Stabilized by interstrand hydrophobic interactions (make tight right hand triple helix)

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12
Q

What are Transport Proteins?

A

membrane-spanning proteins that transport polar or charged molecules in and out of cell
●generally all transmembrane proteins are transport proteins

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13
Q

What are the two classes of transport proteins?

A

Passive and Active

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14
Q

Passive Transport Proteins

A

●Do not require energy to transport molecules across membrane
●in response to chemical gradients (high to low concentrations)
●examples: porins and ion channels
●controlled by amino acids in transport
●static!!

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15
Q

Active Transport Proteins

A

●Require energy to induce conformational change in protein to open or close gated channel
●pump small molecules or ions against concentration gradient
●Energy comes from ATP hydrolysis or Ionic gradient
●Example: Ca2+ ATPase transporter protein
●not static

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16
Q

What are Cell Signaling Proteins?

A

important for communication and includes receptors

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17
Q

What are Receptors?

A

●proteins that function for communication
● most important drug targets
●control and communication primarily come from brain and spinal column

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18
Q

Cell-Cell Communication with neurons

A

●brain sends messages as electrical pulse, travels down nerve cell (neuron) toward target
●Neurons don’t directly touch target, message carried across gap by neurotransmitters (always outside the cell)
●Binds to specific receptor on the cell membrane of target, leads to cascade of secondary effects (signal transduction cascade)
●Causes flow of ions across membrane or switches on and off enzymes inside target cells

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19
Q

Cell-Cell communication with hormones

A

●Chemical messenger, travel in blood, travel farther, travel bilayer (they are non polar)
●Binds and causes conformational change to switch on receptor molecule and message is received

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20
Q

What are the three different types of membrane-bound receptors?

A

ion channel receptors, G-protein-coupled receptors, and Kinase-linked receptors

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21
Q

Ion-Channel Receptors

A

●Complexes made of 5 protein subunits that transverse (transmembrane protein) the cell membrane (quaternary structure)
●hydrophilic tunnel (outside nonpolar, inside polar)
●receptor is part of 1 of the protein subunits
●uses regular nonpolar AA’s because it is small size and linear
●neurotransmitter to ion channel= fast response

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22
Q

G-Protein-Coupled Receptors

A

●Largest class of receptors, biggest drug target
●Globular protein with 7 transmembrane regions (hydrophobic and helical in shape), known as 7-TM receptors
●Examples: adrenergic receptors (adrenaline)
●Activated by hormones and slow-acting neurotransmitters
●GCPRs activate G-protein (signaling protein) which will activate/deactivate membrane bound enzymes or trigger production of secondary messengers

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23
Q

Angiotensin II Receptor

A

●Example of GPCR
●Angiotensinogen -> Angiotensin I (decapeptide) -> Angiotensin II (tetrapeptide)
●Messager binds to receptor, activates Angiotensin II by opening site of receptor for G-protein to bind, causes signal transduction that lowers BP

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24
Q

Kinase-Linked Receptors (KLRs)

A

●Phosphorylation
●Can be Tyr, Ser or Thr
● enzyme and receptor
●Reversibly phosphorylates proteins at Ser and Thr amino acid residues on downstream target proteins in response to upstream receptor activation signals
●critical role in regulating cell differentiation, proliferation, survival, metabolism, and migration
●important for anticancer
●activated by large number of hormones, growth factors, and cytokines
●Loss of function=developmental defects or hormone resistance
●overexpress= cancer (more receptors= more responses)

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25
Q

Domains of KLRs

A

●Ligand binding domain outside cell
●single membrane-spanning domain
●tyrosine kinase domain inside cell

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26
Q

Examples of KLRs

A

Mitogen-activated protein kinase, protein kinase A, insulin receptor, phosphoinositide-3 kinase

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27
Q

What is the binding result of KLRs

A

●receptor dimerization with adjacent receptor, causes tyrosine kinase domain to become active by conformational change when they come together
●Autophosphorylation: receptors phosphorylate each other on multiple tyrosine/ser/thr sites (need ATP to do it)(enzyme is not active until dimerization happens)
●Can then bind to other proteins (SH2 proteins) that specifically recognize the phosphorylated tyrosines

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28
Q

What are Genomic Caretaker Proteins?

A

●they maintain the integrity and accessibility of genomic information
●Important for repairing mutations in DNA reproductive cells (inherited by offspring)
●Includes DNA replication, repair, and recombination proteins (DNA polymerase, DNA ligase, topoisomerase, DNA primase, and RNA polymerase)

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29
Q

What is DNA ligase

A

●Enzyme that joins DNA strands together by forming phosphodiester bond
●Joins Okazaki fragments together during replication
●Used in DNA repair pathways

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30
Q

What is DNA primase?

A

Creates RNA primer for the polymerase to bind to

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31
Q

What does topoisomerase do?

A

●unwinds DNA
●relieves supercoil by cutting in 1 or 2 places

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32
Q

Ivosidenib

A

●metabolism drug target
●isocitrate dehydrogenase-1 inhibitor
●anticancer drug
●first in class drug

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33
Q

Methotrexate

A

●metabolism drug target
● inhibits enzymes responsible for nucleotide synthesis (this prevents cell division)
●anticancer

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34
Q

Fluorouracil

A

●metabolism drug target
●inhibits thymidylate synthase
●anticancer

35
Q

What protein class is the most targeted by drugs?

A

Cell Signaling

36
Q

What is tubulin a huge target for?

A

●Cancer
●drugs can stop tubulin extension or messes w/ attachment (leads to apoptosis at mitotic checkpoint

37
Q

Vinca Alkaloids

A

●Structural drug target
●anticancer
●second largest
●VBL and VCN

38
Q

Taxel

A

●Paclitaxel and docetaxel
●Structural drug target
●anticancer

39
Q

Eribulin

A

●Structural drug target
●Natural produce is halichondrin B
●Smaller and more soluble
●Anticancer

40
Q

Digitoxin

A

●Transport drug target
●ATPase inhibitor
●used to treat congestive heart failure (makes heart contract more)

41
Q

TKR

A

●Cell Signaling drug target
●Anticancer
●Examples of KLR

42
Q

What are examples of drug-targeting GPCRs?

A

histamine receptor blockers (allergy), opioid agonists, beta-blockers (high blood pressure), and angiotensin receptor blockers

43
Q

Cyclosporine

A

●Cell signaling drug target
●immunosuppressant (for organ transplant)
●Calcineurin inhibitor (GPCR receptor)

44
Q

Prazosin

A

●Cell Signaling drug target
●treats hypertension
●alpha-adrenergic blocker
●GPCR example

45
Q

Vasopression

A

●Cell Signaling drug target
●BP medication
●targets multiple GPCRs

46
Q

What are Genomic Caretaker proteins important drug targets for and what do they disrupt?

A

●important for anticancer
●Transcription/Translation Disruptors

47
Q

Etoposide

A

●Genomic Caretaker drug target
● natural protein is podophyllotoxin
●Disrupts TOPII
●anticancer

48
Q

Doxorubicin

A

●Genomic Caretaker drug target
●anticancer
●Disrupts TOPII

49
Q

Camptothecin

A

●Genomic Caretaker drug target
●anticancer
●Topotecan and Irinotecan
●Disrupts TOPI

50
Q

What happens is TOPII or TOPI are not functioning?

A

DNA damage accumulation that leads to apoptosis

51
Q

DNA Repair Pathway Assassins

A

●Trabectedin: binds to minor groove (not reversible) -> DNA replication or transcription halted -> apoptosis
●first tries to repair with DNA repair
pathways -> proteins involved in DNA
repair are inhibited because it binds to
part of the molecule -> apoptosis
●multiple mechanisms of action
●PARP inhibitors (Olaparib): treat gBRCAm metastatic breast cancer
●CDK inhibitors (Ibrance): cancer therapy, treat HR-positive and HER2-negative breast cancer

52
Q

Hemoglobin

A

●transport oxygen from lungs through circulatory system
●major protein in blood cells

53
Q

Myoglobin

A

●storage depot for oxygen (saves it)
●concentrated in muscles (stationary in muscles)

54
Q

What are structural similarities for hemoglobin and myoglobin?

A

●globin fold: eight alpha helices (similar to 4 helix bundle)
●bind oxygen reversibly to Fe2+ in porphyrin ring tightly bound to protein

55
Q

Heme

A

●Fe2+ porphyrin complex
●prosthetic group: non-amino acid portion of certain protein molecules
●necessary since no amino acids side chains can reversibly bind oxygen

56
Q

What is porphyrin?

A

group of heterocyclic, macrocyclic, organic compounds, composed of four modified pyrrole subunits

57
Q

Heme in Myoglobin

A

single polypeptide chain with one heme group

58
Q

Heme in Hemoglobin

A

●four polypeptides (two identical alpha and two identical beta subunits) with four heme groups
●considered a dimer of heterodimer (a1b1, a2b2) (functional significance for subunit interactions)

59
Q

What is a ligand?

A

ions or neutral molecules that bind to a central metal atom or ion in a larger molecule (protein)

60
Q

Ligand-Protein Interactions

A

●Ligand binding is reversible (noncovalent interactions)
●binding induces or stabilizes structural conformations in target proteins (alter protein affinity for ligand)
●Effector molecules can alter equilibrium between ligand-bound and ligand-free proteins (increase and decrease affinity)

61
Q

Ka

A

●association constant
●P+L -> PL

62
Q

Kd

A

●dissociation constant
●PL -> P+L
●larger Kd= lower affinity because larger products (P and L do not want to be together) and smaller amount of reactants

63
Q

Fractional Saturation

A

●θ=fraction of protein binding sites that are occupied
●= Occupied binding sites/ Total binding sites
●can rearrange to L/L+Kd

64
Q

Fraction Saturation graph facts

A

●ligand concentration=Kd, then θ=0.5
●θ vs [L] makes a hyperbolic curve
●Simple protein-ligand interaction
●Kd can be determined by concentration of ligand at 0.5
●think amount of ligand needed to saturate 50% of proteins
●higher affinity=less concentration needed to saturate 0.5
●IF graph does not plateau at 100, you need to do Kd based on half of where it plateaus

65
Q

What can we learn from Kd

A

●what factors influence protein’s interaction with ligand to generate stronger or weaker binding
●which ligands are physiologically important
●the conditions that affect protein’s function

66
Q

Fraction Saturation for Myoglobin

A

●θ vs pO2
● hyperbolic, simple
●more active= release O2, saturation drops
●rest= higher saturation, readily for muscle activity because O2 is used to form ATP

67
Q

Fraction Saturation for Hemoglobin

A

●θ vs pO2
●sigmoidal curve, not simple
●sharper decrease in saturation at low oxygen
●Saturation gets lower away from lungs because it gives O2 to all the cells that need it
●indicates positive cooperative binding

68
Q

Cooperative binding

A

●binding of the first ligand to the protein complex facilitates the binding of additional ligands on same protein
● need quaternary structure
●Myoglobin can not do cooperative binding because it only has one heme (1 subunit) (no 4 structure)

69
Q

What are the 6 coordination bonds to the Fe2+ in the heme group?

A

●4 planar nitrogen
●proximal histidine: directly coordinates to Fe2+ (covalent)
●distal histidine: hydrogen bonds to O2, stabilize interaction with heme group

70
Q

Deoxyhemoglobin

A

no oxygen in heme, no longer planar, causes pucker

71
Q

Oxyhemoglobin

A

●O2 binding causes the Fe2+ to be pulled into plane of porphyrin ring (proximal moved with it)
● moves F8 Histidine and backbone (induces conformational change in entire molecule)

72
Q

Cooperative Binding with small movements

A

●small movements in F helix from O2 binding causes entire protein complex to change noncovalent interactions at interface of alpha and beta subunits
●small structural changes in one region -> large structural changes in entire hemoglobin molecule
●alter O2 affinity in all 4 globin subunits

73
Q

T (tense) State

A

●Oxygen is unbound
●deoxyhemoglobin
●larger hole in center

74
Q

R (relaxed) State

A

●Oxygen is bound
●oxyhemoglobin
●aB dimer rotated 15 degrees from the other
●fourth O2 binds with 100x more affinity than first O2 does (different affinity from T)

75
Q

Concerted Model

A

●Protein exist in either T or R state (exist in equilibrium)
●T favored when little for no ligand is bound
●Ligand binding to single subunit in tetrameric protein complex helps stabilize R state (increases population of R state)
●Ligand bind to T or R, but only high affinity for subunits in R state
●No mixture in hemoglobin, only T or R, whole molecule changes at once

76
Q

Sequential Model

A

●ligand binding of one subunit of tetrameric protein induces conformational change so nearby subunits are more likely to bind ligand and shift to R state
●can be mixture of T and R in one molecule of hemoglobin

77
Q

Allosteric Effectors

A

●Don’t need cooperative binding
●describes ability of biological molecules to transmit effects of binding spatially through the protein to other sites
●Molecules that alter structural conformation to favor one state over another

78
Q

Hemoglobin Allosteric Effectors

A

●Oxygen (positive: encourage T -> R)
●2,3-biphosphoglycerate (negative: encourage R ->T):
●over negative effectors: CO2, H+

79
Q

H+ allosteric effector

A

●lower pH (more H+)= more stabilized T because higher Kd (more dissociation of oxygen and hemoglobin)
●hemoglobin less likely to bind to Oxygen
●Why? aerobic respiration creates acid (H+) during exercise and we need more O2 to cells. H+ stabilizes T state and oxygen will more efficiently be delivered to cells

80
Q

Bohr Affect

A

●Combine H+ and CO2
●CO2 binds (in form HCO3-) to hemoglobin by forming carbamate group at N-term of alpha subunit
●produces another H+ that contributes to reducing hemoglobin’s affinity for oxygen
●Why? hemoglobin carries CO2 to lungs for exhale, won’t bind oxygen, favor T-state

81
Q

2,3-BPG

A

●Binds to hole in T state, traps hemoglobin in T state
●One molecule of 2,3-BPG binds to one hemoglobin, prevents oxygen from binding to any of the 4 subunits
● binds to beta subunits with ionic interaction with 3 positively charged residues on each beta subunit (2 subunits)(His2, Lys82, His143)
●Fetal hemoglobin: beta subunit replaced with gamma (y) subunit, His143 mutated to Ser143 -> causes 2,3-BPG to not be able to bind
●WHY? high altitude= want oxygen to be easier to deliver (favor T)

82
Q

The insulin receptor is an example of what type of protein.

A

Kinase-Linked Receptor

83
Q

Which of the following proteins are predominately drug targets for anticancer drugs

A

Genomic caretaker proteins, kinase-linked receptors, structural proteins

Biochemistry I (3 decks)

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