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

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.

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)  CO 2 + H 2 O + 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 + ] = 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? Actual (not standard) concentrations

Why use ATP? ATP –  G’ o hydrolysis = kJ/mol –  G may be even more negative! Glycerol-3-phosphate –  G’ o hydrolysis = -9.2 kJ/mol Why difference?