Thurs review• Signal transduction mechanisms

– Gated ion channels• Neuronal signaling, muscle contraction• nACh receptors, Na+ channels, K+ channels, Ca+2 channels

– Membrane receptor enzymes• Insulin receptor

glucose transporters on plasma membrane glycogen synthesis– Gene expression regulation

synthesis of enzymes involved in glycolysis, amino acid transport, lipogenesis…

synthesis of enzymes involved in gluconeogenesis, lipolysis…

– Nuclear receptor • Steroids

Steroid/Nuclear receptors

• Steroids hydrophobic– In serum protein bound– Simple diffusion across

membrane – Bind to receptor proteins in

nucleus trigger conformational change

• Ligand binding domain• DNA binding domain

– binds to a regulatory sequence in DNA (hormone response element)

Steroid/Nuclear receptors

• How does steroid binding modify gene expression?

•No change in DNA binding affinity or specificity

•Induces binding of a ‘coactivator’

• modifies chromatin by loosening histones from DNA

Steroid/Nuclear receptors

Stryer ‘Biochemistry’ 2004

Steroid/Nuclear receptors

• Agonists– Molecules that bind to

receptor and trigger response

• Anabolic steroids– Agonists of androgen

receptor

– Stimulates gene expression lean muscle mass

O

CH3

CH3O

Androstendione O

CH3

CH3

Dianabol (synthetic androgen)

OH

CH3

Steroid/Nuclear receptors

• Antagonists– Molecules that bind to

receptor but do not trigger response

• Like competitive inhibitors (enzymes)

– Tamoxifen—estrogen receptor antagonist

– Slows growth of cancer cells that depend on estrogen for growth

Stryer ‘Biochemistry’ 2004.

HO

CH3O

Estrone

Bioenergetics and Metabolism

• Metabolic pathways serve 4 functions:– To obtain chemical energy

• Solar energy (phototrophs)• Energy-rich nutrients (chemotrophs)

– To convert nutrients into molecules that the cell needs– To polymerize monomers into polymers – To synthesize and degrade biomolecules required for

cell function

• Central/major metabolic pathways are common across species

Metabolism

• Sum of all chemical transformations in cell/organism

• Catabolism– Degradation of carbs, fats, proteins, etc – Energy-releasing

• Fuel (carbs) CO2 + H2O + energy (ATP or reduced cofactors)

• Anabolism– Biosynthesis of complex molecules (proteins, nucleic

acids)– Energy-requiring (energy from catabolism)

Metabolism

• Anabolism– Divergent pathways

• Catabolism– Convergent pathways

• Close relationship– Product of one is

substrate for other

– Same intermediates

Metabolic regulation

• Individual enzyme regulation—how?

• 1 enzyme difference in pathways

• Competing metabolic pathways in different cell compartments

• FA catabolism mito

• FA biosynthesis cytosol

– Each pathway has one ~irreversible step• Substrate availability

Metabolism

• Most reactions are of 5 major types

1. Oxidation-reduction

2. Making/breaking of C-C bonds

3. Isomerizations/rearrangements

4. Group transfer reactions

5. Hydrolysis

• All pathways/reactions must obey laws of thermodynamics (-G)

G’o

In vivo reactions do not proceed under ‘standard biochemical’ conditions

G’o standard transformed free energy

•characteristic of reaction under standard conditions (1M, 298 K, 1 atm)

–Biological reactions…..pH 7, [H+] = 10-7 M

•[Mg+2]= 1 mM

G and G’o

G = G’o + RT ln

At equilibrium G = 0 and G’o = -RT ln K’eq

– Biological reactions will be spontaneous when–G ….even if G’o is positive

– How do we make a reaction with a + G favorable?

ba

dc

BA

DC

][][

][][ Actual (not standard) concentrations

Why use ATP?• ATP

G’ohydrolysis = -30.5 kJ/mol

G may be even more negative!

• Glycerol-3-phosphate– G’o

hydrolysis = -9.2 kJ/mol

• Why difference?HO

H2C

CH

H2C

O

P

OH

O

O-

O-

Glycerol-3-phosphateG'ohydrolysis = -9.2 kJ/mol