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LAST MEDCHEM OF UR LIFE > 39 - Protein Turnover > Flashcards

39 - Protein Turnover Flashcards

1
Q

Major Pathways of
PROTEIN TURNOVER

A
  • *Lyosome**
  • *Vacuolar** –> Autophagy
  • *Proteasome**
  • *Cytoplasmic** –> Ubiquitin-Proteasome System

minor pathway:
capsases = cysteine proteases
involved in apoptosis

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2
Q
  • *Bortezomib = Velcade**
  • *Proteasome Inhibitor’s**

BINDING / MoA

A

Tetrahedral Adduct
occupy peptide binding pockets –> Nu- N-terminal throenine

Good Selectivity

  • *REVERSIBLE BINDING**
  • *Nucleophilic attack** –> binds to the B5 of PROTEOLYTIC CORE
  • *BORON**
  • *readily accepts electrons** & can interconvert w/ ease
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3
Q

Proteasome Function

3 specificities:
Chemotrypsin -Like

Trypsin -like

Caspase - like

A

Substrate docks @ LID/CAP where
Ub-Chains are recognized
proteasome undergoes
Major CONFORMATIONAL CHANGE
which also removes the Ub-units

THREONINE PROTEASE
activates in the proteolytic core
Degradation / breakdown @ the CORE

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4
Q

LYSOSOMAL STORAGE DISEASES
LSD

A
  • *Substrate accumalation** –> chronic/progressive clinical syndromes
  • *RARE**, recessively inherited

MAINLY DUE TO:

  • *DEFICIENCY in_ _LYSOSOMAL HYDRALASES**
  • but also some non-enzymatic proteins*

Most LSD’s are associated with severe neurdegeneration in:
childhood / mental decline / cognitive problems

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5
Q

Short-Lived Proteins

A

broken down by Proteasomes (Cytoplasmic) via Ub

Regulatory Proteins

Cell-Cycle Regulators

Damaged/Misfolded Proteins

Minutes –> Hours

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6
Q

Ixazomib

A

Ninlaro

Oral Proteasome Inhibitor
prodrug

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7
Q

_3 Methods of RESISTANCE
to Proteasome Inhibitors_

KNOW THIS

A

“M-O-A”

MUTATION
B5- results in less affinity

OVEREXPRESSION
B5–> compensate by adding more binding sites

Activation of AUTOPHAGY
Histone deacytylase 6 -> promote cell survival

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8
Q

Ubiquination Steps

A
  • E2 + E3 BIND to the DENATURED PROTEIN
  • E1 grabs / activates / binds Ub
    • –> brings it to the E2
  • E2 conjugates Ub COVALENTLY
    • –> brings it to E3
  • •E3 ligase
    • Ub –> Denatured protein
  • REPEATED
    • The NEXT/2nd Ub –> is bound to the FIRST Ub
      • And so forth….
        • Creating the Ubiquitin code to be read by
          • the UBD proteins
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9
Q

What type of Therapeutic Strategy for LSD?

Help Proteins fold in their functioning conformation
many mutations –> abnormal folding of lysosomal enzymes

A

CHAPERONE THERAPY

Migalstat = Galafold

indicated for
Fabry Disease

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10
Q

Pharmacologic Chaperone Therapy
for LSDs

ADV / DISADV

A

Migalstat = Galafold –> Fabry Disease

ORALLY / no immune rxns
BBB crossing

DISADV:
Drugs are mutation-specific –> some mutations are unresponsive
PC bind to catalytic sites –> dosing is difficult

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11
Q

What DECIPHERS the Ubiquitin Code
&
Links the substrates to downstream processes?
like
proteasomal degradation / lysosomal degradation
or
Non-proteolytic processes

A

UBD PROTEINS

Ub-Binding Domain Proteins

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12
Q

Glycocalyx

A

Polysaccharide-based coating
on the INNER SIDE of the
Lysosomal membrane
that PROTECTS it from self-digestion by the
lyosomal enzymes (acid hydrolases)

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13
Q

Chloroquine

Indication // Target / MoA

A

Cancer Treatment by targetting AUTOPHAGY

LYSOSOMOTROPIC DRUG
compound that is able to penetrate Lysosome / target them
chloroquine = weak base –> protonated & trapped in lysosome
and
DECREASES LYSOSOMAL pH -> 4.5
which then inhibits autophagic degradation
–> need 5.0 for optimal fxn

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14
Q

Ubuitin Proteasome System

Stages

A

“Tag & Chew it”

  • *TAG first**
  • *UBIQUINATION** –> targets proteins for degradation
  • *CHEW second**
  • *PROTEASOME** –> degrades
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15
Q

What are UBD Proteins?

A

Ubiquitin Binding Domain Proteins:
various effector proteins that
Recognize / Read the UBIQUITIN CODE
&
link the Ub-tagged protein to different processes such as:
Proteolysis = Proteosome / autophagy
or
non-proteolytic processes

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16
Q

Bortezomib

Brand Name / Target / Indication

A

Velcade

Throenine Proteasome inhibitor
for
Cancer
Multiple Myeloma // Mantle Cell Lymphome

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17
Q

3 APPROVED PROTEASOME INHIBITORS

know this

A

“BCI-VKN”

Bortezomib - Velcade

Carfilzomib - Kyprolis

Ixazomib - Ninlaro

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18
Q

What type of Therapeutic Strategy for LSD?

Good strategy because LSD’s are
Well-Characterized / Single-Gene Disorders

Still Investigational

A

GENE THERAPY

still investigational

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19
Q

Carfilzomib

A

Kyprolis

Proteosome Inhibitor

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20
Q

Long-Lived Proteins

A

Broken down by LYSOSOMES(vacuolar) via Autophagy

HEMOGLOBIN
>100 days

ALBUMIN
>20 days

Structural Proteins = Collagen
> Years

21
Q

What TYPE of Autophagy?

Autophagy INDUCED by STARVATION

Is NON-Selective

A

BULK AUTOPHAGY

Bulk starvation

22
Q

What is the UBIQUITIN CODE?
& what does it recognize?

A

After the substrate is UBIQUINATED
there are different types of
UB LInkages & Chain Lengths

that are read by UBD Proteins
( Ub-Binding Domain )
specificity for distinc linkage/lengths

23
Q

What is the Ub-Proteasome System
essential for?

A

Regulatory Mechanisms:

Cell-Cycle Progression

Signal Transduction

APOPTOSIS / Oncogenesis (cancer)

24
Q

Ubiquitin
Function / Mechanism

A

TAGS protein for protesomal degradation
terminal Glycine + multiple Lysines

“ACL”

  • *E1**
  • *ACTIVATION** of Ub w/ ATP (adenylation
  • *E2**
  • *CONJUGATION** –> transfer
  • *E3**
  • *LIGASE** = brings teh specificity
25
Q

Physiological roles of

Autophagy

A

Maintainance of cellular homeostasis

Body’s response to nutritional stress or starvation

Cellular Remodeling
including adaptation to changes in availble nutrients

Containing Intracellular microbial infections
TB

26
Q

Other Investigational Targets

in Ub-Proteasome System

A

Target E3 Ub Enzyme
instead of the whole proteasome
since it is the most specific –> less toxic

Cross-talk
between autophagy & proteasome

Also for

  • *neurogenerative diseases &**
  • *Immune-mediated disorders**
27
Q
  • *Lyosome**
  • *Structure / Components**
A

Vacuolar System of Protein Turnover
HYDROLASES
for the degradation of specific substrates:
Proteins / Carbs / NA’s / Lipids

GLYCOLYX
a polysacchride-based coating on the INNER side of the lyosomal membrane that protects the organelle from self-degradation

PROTON PUMP
which maintains a ACIDIC LUMEN, pH 5.0

28
Q

SRT = Substrate Reduction Therapy
for LSDs
ADV / DISADV

A

Eliglustat = Cerdelga for Gaugcher disease

ORALLY!
does NOT generate immune reactions
may cross the BBB

Disadvantages:
Currently only available for 2 LSDs

29
Q

FABRY DISEASE
how do we treat?

A

LSD cause by mutations in GLA gene

  • *Enzyme Replacement Therapy**
  • *Agalsidase = Fabrazyme**

CHAPERONE THERAPY
helps enzyme properly fold
Migalstat = Galafold

30
Q

Autophagy CYCLE

A
  • Isolation Membrane
    • Can be a Piece off of the ER (induction)
    • –>ENGULFS CARGO = mitocondria etc
  • Autophagosome
    • Formed once the isolation membrane is ENCLOSED
  • AutophagoLYSOSOME
    • LYSOSOME + Autophagosome
      • Lysosome contains HYDROLASES
    • Degrades material & recycles
31
Q

Which Enzyme in the Ub-Proteasome System
brings SPECIFICITY?

A

E3

they have different specificities
recognize different substrate AA sequences“motifs” @ N/C terminus

32
Q

Proteasome

A

Cytoplasmic pathway of Protein Turnover

ATP-Dependent proteolytic machine

Degrades proteins with HIGH SPECIFICITY from
tagging system = UBIQUITIN

33
Q

CROSSTALK

Between Autophagy / Proteasome

A

Another topic of research:

After UBD Proteins recognize the UB code
they TRANSFER the tagged proteins to EITHER:
Proteasome or Autophagosome

impairment of one can lead /direct to the other

34
Q

Autophagy & Neurodegeneration

A

ALZ / Parkingson’s / Huntington’s disease
pathologies are possibly implicated by

Toxic Protein Aggregates
which can be degraded via AUTOPHAGY

Autophagy Defects –> neurodegeneration
so Autophagy can play a PROTECTIVE role against these diseases

35
Q

Enzyme Replacement Therapy
(used for LSD’s)
Advantages / Disadvantages

A

GAUCHER DISEASE
Imiglucerase / Cerezyme

ERT has been shown to be effective in
Reducing Storage Materials

disadvantages:
IV administration // Immune RXN
Difficulty Targetting to tissues that are not reached through circulation
bone / cartilage / brain

36
Q

Proteasome Inhibitor

(threonine proteasome)

Drug name / Indication

A

Bortezomib = VELCADE

Indicated for CANCER:
Multiple Myeloma & Mantle Cell Lymphoma

37
Q

LYSOSOME
FUNCTIONS

A

Degrade & Recycle BOTH:

Intracellular Material
obsolete components of the cell ITSELF
via Autophagy

EXTRAcellular Material
degrade material that is taken from OUTSIDE of the cell
via Endocytosis

38
Q

What TYPE of Autophagy?

Autophagy that uses UBIQUITIN to tag the protein
todegrade:

Protein Aggregates // Dysfunctional Organells // Invading Pathogens

A

SELECTIVE AUTOPHAGY

Uses UB –> tag protein to degrade:
Protein Aggregates // Dysfunctional Organells // Invading Pathogens

39
Q

Autophagy

A

“Self-Eating”
A function of Vacuolar Protein Turnover

LYSOSOMAL degradation / recycling
of the
cell’s OWN materials/molecules

40
Q

What DRUG targets AUTOPHAGY
for CANCER TREATMENT
clinical trials still

A

CHLOROQUINE & Hydroxychloroquine
as Lysosome Inhibitors

Autophagy Inhibition can be BOTH Bad & Good
since it is used to:
keep cancer cells alive
as well as
immune response to kill cancer cells

41
Q

What type of Therapeutic Strategy for LSD?

  • *Compensate** for metabolic defects through
  • *infusions of RECOMBINANT ENZYMES**
A

ERT** = **Enzyme Replacement Therapy

USED FOR BOTH DISEASES

  • *Gaucher Disease**
  • *Cerezyme** = Imiglucerase
  • *Fabry Disease**
  • *Agalsidase = Fabrazyme**
42
Q

Therpeutic Strategies for LSD’s
Lysosomal Storage Diseases

A

Goal is to restore balnce between substrate influx & degradation
ORPHAN DRUGS –> developed to treat a rare condition

Do NOT CURE,
but just stabilize organ fxn & slow progression of disorder

ERT = Enzyme replacement Therapy

SRT = Substrate Replacement Therapy

Chaperone Therapy

Gene Therapy

43
Q

26S Proteasome
Structure

A

2 Halves + 7 proteolytic sites
that form a Barrel / Cylinder

2 Outer Regulatory Caps

2 Inner Proteolytic Cores

44
Q

Protein Turnover / Recycling

A

BALANCE
between Protein Synthesis & Degradation
crucial for cellular activity

Most protein are synthesized from AA’s
are from degradation of pre-existing proteins
300-500g proteins / day vs 60-80g digested

45
Q

Implications of AUTOPHAGY DYSREGULATION

A

CANCER
Good & Bad Autophagy –> survival vs immune response

NEURODEGENERATION
Autophagy degrades Toxic-protein-aggregates which are implicated in
ALZ / Parkinson’s / Huntington’s disease

Some MYOPATHIES
primary symptom is muscle weakness do to dysfunction in muscle fiber
–> cardiac diseases

46
Q

Gaucher Disease
how do we treat?

A

Lysosomal Storage Disease = LSD

Enzyme Replacement Therapy
for type 1 –> replaces the enzyme
Eliglustat = Cerdelga

Substrate Replacement Therapy
was later approved –> inhibits the enzyme
Imiglucerase = Cerezyme

47
Q

What type of Therapeutic Strategy for LSD?

Slows the production of storage material
instead of degrading it
reduce the substrate from getting into the lysosome first
Biosynthesis Inhibitor

A

SUBSTRATE REDUCTION THERAPY
for LSD

Eliglustat = Cerdelga
inhibits ceramide GT

for Gaucher Disease

48
Q

Threonine protease = COVALENT CATALYSIS

  • The goal is to CLEAVE / HYDROLYZE an amide bond
    • Difficult to do because of delocalization
      • Done through COVALENT catalysis only
  • Forms a Tetrahedral intermediate = forms an ester (easier to cleave than an amide)
    • •–> Acyl –Enzyme intermediate
      • –> HYDROLYSIS by the acyl enzyme
        • Uses WATER
A
49
Q
  • *26S Proteosome**
  • *Facts**
A

COVALENT CATALYSIS

  • *Proteolytic Sites** can CLEAVE almost ANY sequence
  • but they are*
  • *VERY SPECIFIC** –> will Only target Ub-TAGGED Proteins
  • does not harm untagged proteins*

Proteolytic activity is only at the CENTER and access is
Sterically Controlled

LAST MEDCHEM OF UR LIFE (11 decks)

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