Biochem

Inhibitor

blocks the receptor- ligand interaction.

Humira
- drug name
- treatment for ?
- importance

(adalimumab)= biologic monoclonal antibody; used to treat RA, psoriatic arthritis, ankylosing spondylitis, Crohns, UC [has been a top selling drug for the past 7 years]

Sx

________: fever, fatigue, easy bleeding, anemia, infection, splenomegaly, arthralgia.

GPCR
- features
- genes

7 TM protein made from a single polypeptide chain (NH3 outside of cell, carboxyl end is cytoplasmic), 700+ genes in human genome.

Antagonist

blocks the action of the agonist.

PIP3

important lipid second messenger which regulates many cellular processes

RTK
- basic mechanism

bind protein ligands w /high affinity → dimerization & autophosphorylation → + activate /recruit of effectors to generate signaling cascade → change cellular processes

energy sources

Describe anaerobic reactions: Immediate ________, stored ATP and Fast energy source of glycolysis ending in lactate.

Agonist

molecule that activates a receptor to create a biological response (some agonists elicit stronger responses than the endogenous ligand)

cellular metabolic programs

Describe ________: growth and burning of energy.

Cell surface

TM proteins formed by hydrophobic aa arranged in helical structure

Function

utilize secondary messenger system/signaling cascade

Intracellular

cross PM w/o help; receptor-hormone complex → bind hormone response element on DNA → influence transcription of specific genes

Function

bind to HRE & directly influence transcription of specific genes

Described receptor types

transmembrane localization, subunit structure and function; enzymatic activity, intracellular receptors

Ligands

photons to proteins

Subunits

heterotrimeric, alpha, beta, gamma subunits

Function

same signaling molecule can interact w/ different receptors & trigger distinct responses

alpha i

--| AC → decrease cAMP ==> inhibitory (phospholipase, phoshodiesterases)

alpha q

→ PLC → PIP2 → DAG & IP3 → SR release of Ca++ → + PKC ==> stimulatory

B

Secretin receptor family

C

Metabotropic glutamate/pheromone

RTK
- features
- genes

single TM protein, 58 genes; ligand activated enzymatic activity = autophosphorylation → signaling cascade

alpha s

→ +AC → increase cAMP → PKA→ CREB ==> stimulatory

Class 1 PI3 Kinase

phosphorylates inositol ring of PIP2 @ 3rd position → PIP3

Diabetes mellitus

insulin

Chronic myelogenous leukemia/CML

too many myeloblasts in the blood & bone marrow

Sx

fever, fatigue, easy bleeding, anemia, infection, splenomegaly, arthralgia

Tx

Gleevec 2001, first kinase inhibitor drug

Drug discovery

screening chemical drug libraries using several assays (testing drug & target, repeat and validate)

Basic research

viral mechanism, viral entry infection, immune response

Drug discovery

providing therapeutic options (vaccines, anti-virals, antibody, anti-toxin, enhance immunity)

Questions

Slide 20

Describe anaerobic reactions

Immediate energy sources, stored ATP and Fast energy source of glycolysis ending in lactate

Described sustained energy sources

glycolysis ending in pyruvate and beta oxidation of fats

Describe cellular metabolic programs

growth and burning of energy

steroid hormones control 6 major things

1. metabolism
2. inflammation
3. immune functions
4. water/salt balance
5. sexual characteristics
6. response to illness/injury

steroids
- classification

5 classes
corticosteroids or sex hormones

HRE
- domains
- used by which receptors

Hormone response element = specific sequence of DNA
N-terminal domain
DNA binding domain
Hinge region
Ligand binding domain
C terminal domain

Intracellular receptors!!

Steroids
- enter the cell how?

Diffusion

Hormones which require transport system

Thyroid hormones
Vitamin D
Retinoic acid/retinoid

Hsp 70

Heat shock protein 70
binds to cytosolic hormone receptor & prevents it from entering the nucleus

+ hormone bound --> Hsp 70 released --> hormone - receptor --> nucleus --> + HRE ==> change gene expression

Steroids are released into ___ then pass through the _____ to bind _____.

Steroids are released into blood then pass through the plasma membrane to bind intracellular receptors.

After steroids bind internal receptors, they ___ and become ___ to _____.

After steroids bind internal receptors, they change shape, and become transcription factors to change gene expression.

Signal transduction

refers to post receptor signaling cascade, signal propagation, effectors, transducers, second messengers (intracellular events initiated by receptor activation relayed to inside of cell)

Integration

effectors or transducer proteins
- cell receives input from many resources --> combines them --> determine how to respond

Response

change in cellular process
- ex. proliferate, apoptosis, secretion (send signals to other cells)

hormone groups
- major differences (3)

- molecular type (diffusible into cell or not)
- synthesis
- size

Hormone groups
- 3 classes

I. Lipid derived aka steroid hormones
II. Amino acid derived
III. Peptide/protein hormones

Estradiol
- which class of hormones
- intracellular or cell membrane R

lipid derived/steroid
- nuclear hormone w/ intracellular receptor

insulin
- which class of hormones
- intracellular or cell membrane R

peptide/protein hormone
- single pass TM protein receptor on cell membrane (RTK)

epinephrine
- which class of hormones
- intracellular or cell membrane R

amino acid derived hormone
- GPCR

Cell surface transmembrane receptors
- features of TM domains

formed by hydrophobic amino acids arranged in helical structure

Agonists
- example

opioids
weakest to strongest: codeine < morphine < heroin < fentanyl

oxycodone is also an agonist for opioid receptors

% of drugs alter GPCR function

50% of current drugs alter GPCR function

Largest group of GPCRs

Rhodopsin like receptors (Class A/1) (85% of GPCRs)
* best studied

GPCR classes

A: Rhodopsin like
B: Secretin receptor family
C: Metabotropic glutamate/pheromone

GPCRs have ___ membrane topology, structure and mechanism of signal transduction, __ major classes, and ________ between classes.

common
3
low sequence homology

PTEN

renowned tumor suppressor gene
PIP3 --> PIP2

Insulin receptor
- type
- basic mechanism

RTK

- Insulin finds target cell (which expresses insulin receptor) --> binding to RTK is high affinity
- Autophosphorylation --> activated
- IRS-1 activation
- PI3 kinase activation (IR KINASE ACTIVATED --> initiates cascade)
- PIP3 formation
- PDK-1 activation
- Akt kinase activation
- GLUT 4 activation (moves to cell membrane)
--> pulls glucose out of blood and into cells

After you eat a meal, how do you get glucose into cells?

blood glucose increases --> pancreas secretes insulin --> IR kinase --> + cascade ==> GLUT 4 and cell uptake of glucose from blood; protein phosphatase also activated --> + glycogen synthase

CML
- pathophysiology
- signs & symptoms (7 main ones)

Philadelphia chromosome (translocation 9/22)
--> too many myeloblasts (immature blood cell) in the blood & bone marrow
- progressive, but slow growing cancer
- sx: fever, fatigue, easy bleeding, anemia, infection, splenomegaly, arthralgias

CML
- treatment

Gleevec
FDA approved in 2001
inhibits BCR - ABL
(ABL on nL C9; BCR on nL C22 --> prevents joining of C9 & C22)

Beta adrenergic receptor
- receptor type
- ligand
- mechanism
- opposite reaction

- GCPR
- epinephrine (need to get more glucose in blood !)
Epi --> + G alpha S --> + AC --> increase in cAMP --> PKA --> PK --> P-glycogen-phosphorylase --> glycogen breakdown

PKA also inhibits glycogen synthetase

Opposite reaction: insulin --> + RTK --> storage of glucose in cells

PI3K fxn

PIP2 --> PIP3

opposite of PTEN which turns PIP3 --> PIP2

Thermodynamics

chemical changes in living organisms follow the law of thermodynamics

Free energy change

maximum energy made available to do work when a chem rxn occurs

Basic biochemical principles

1. Covalent bonds - heterolytic/homolytic cleavage
2. Many reactions include nucleophiles and electrophiles

Homolytic cleavage

each atom leaves the bond as a radical, carrying one paired electron

Heterolytic cleavage

one atom retains both bonding electrons

Nucleophiles: donate or accept electrons

nucleophiles capable of donating electrons

Electrophiles: donate or accept electrons

electrophiles seek electrons

Carbon atoms: electrophile or nucleophile

can act as either electrophile or nucleophile