Meat Biotechnology – Applications in Pork Quality Muscle Targeted Growth Promotants – Mode of Action of Beta Agonists
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Meat Biotechnology – Applications in Pork Quality Muscle Targeted Growth Promotants – Mode of Action of Beta Agonists Deana Hancock, Diane Moody, Dave Anderson Elanco Animal Health Reciprocal Meat Conference, June 19, 2006 Pharmacological Activity: Beta•Adrenergic Agonist What is a beta•adrenergic agonist? A beta•adrenergic agonist (b•agonist) binds to and activates beta•adrenergic receptors (b•AR) that are found on the surface of many different types of cells in the body. G A G M L V L V G P A A A L P D G Beta Adrenergic P G L E N S S A S A T A N D P V L R A Y Receptors L L P L C K P A S P S R C P A P R C A A D S E F E S D E Y G V R E P W S S E P L T H L S R F E Q Q N F V W G F A R A P T W C R A K D A E L W Y V R G V V I W A V L (1) M (3) W H (5) I N (7) F G T T S L A L L G A S L M A F V M F V S F F A D I N L P V V P V F V L Shaded AA's are V I L C L F S V L P L W Transmembrane L G L S F V T Y W G conserved across the L I M A V L V P C Y A Domains V L A L V E I S S G A S A D A I S I C L V F T N human b1, b2 and b3 T L M A N A L W V A G M F AR's (31%) V L C V T F I N V M S C V I P I I I V I V Y G A I A L L L I A (2) F L L (4) G R (6) T Y K N D R V K C A L R F A R T T G L L C Y R R K S Q C A R R P L A F A R L E Q P D F R K A L T Q A R A E A T Q R R I K P H T L L S A R R D G A H R R T Q R L V A G L V S C Circled AA's are S K P R A L S P P Q K D conserved across F R Y I R A R G D D D D R P D V V G A D K G G N P P S the b AR of S A P G A S T 1 C A E L P humans, pigs, R L L P R P P E A F G N W R and sheep (80%) L A A A A G C G A G G A A A R P A A T D P G P P P S S S L E S K A P D D E P A S V C R F R P P G A P P P S P S P S V A Mersmann, 1998; J. Anim. P P Moody et al., 2000; Farm Animal Met. & Nutr. Sci. 76:160 J.P.F. D'Mello (Ed.) G A G M L V L V G P A A A L P D G Beta Adrenergic P G L E N S S A S A T A N D P V L R A Y Receptors L L P L C K P A S P S R C P A P R C A A D S E F E S D E Y G V R E P W S S E P L T H L S R F E Q Q N F V W G F A R A P T W C R A K D A E L W Y V R G V V I W A V L (1) M (3) W H (5) I N (7) F G T T S L A L L G A S L M A F V M F V S F F A D I N L P V V P V F V L V I L C L F S V L P L W Transmembrane L G L S F b AR lacks the V T Y W G 3 L I M A V L V P C Y A Domains V L A L phosphorylation site V E I S S G A S A D A I S I C L V F T N T L M A in domain 4 N A L W V A G M F V L C V T F I N V M S C V I P I I I V I V Y G A I A L L L I A (2) F L L (4) G R (6) T Y K N D R V K C A L R F A R T T G L L C Y R R K S Q C A R R P L A F A R L E Q P D F R K A L T Q A R A E A T Q R R I K P H T L L S A R R D G A H R R T Q R L V A G L V S C S K P R A L S P P Q K D F R Y I R A R G D D D D R P D V V G A D K G G N P P S S A P G A S T C A E L P R L L P R P P E A F G N W R L A A A A G C G A G G A A A R P A A T D P G P P P S S S L E S K A P D D E P A S V C R F R P P G A P P P S P S P S V A Mersmann, 1998; J. Anim. P P Moody et al., 2000; Farm Animal Met. & Nutr. Sci. 76:160 J.P.F. D'Mello (Ed.) OH OH H N Beta Agonist HO b Adrenergic Receptor b AR Membrane Gs AC Terminology b AR Beta Adrenergic Receptor Gs G Stimulatory Protein AC Adenylate Cylase Beta Agonist OH OH H b Adrenergic Receptor N HO b AR Membrane Gs AC Terminology b AR Beta Adrenergic Receptor Gs G Stimulatory Protein AC Adenylate Cylase Beta Agonist OH OH H b Adrenergic Receptor N HO b AR Membrane Gs AC Terminology b AR Beta Adrenergic Receptor Gs G Stimulatory Protein AC Adenylate Cylase Beta Agonist OH OH H b Adrenergic Receptor N HO b AR Membrane Gs AC ATP cAMP Terminology b AR Beta Adrenergic Receptor Gs G Stimulatory Protein AC Adenylate Cylase ATP Adenosine Triphosphate cAMP Cyclic Adenosine Monophospate Beta Agonist OH OH H b Adrenergic Receptor N HO b AR Membrane Gs AC ATP cAMP PKAinactive PKAactive Terminology Enzyme Phosphorylation b AR Beta Adrenergic Receptor Gs G Stimulatory Protein AC Adenylate Cylase ATP Adenosine Triphosphate cAMP Cyclic Adenosine Monophospate PKA Phosphokinase A Beta Agonist OH OH H b Adrenergic Receptor N HO b AR Membrane Gs AC Metabolic Modification FAT CELL ATP cAMP Fat synthesis Fat breakdown PKAinactive PKAactive MUSCLE CELL Protein synthesis Terminology Enzyme Phosphorylation b AR Beta Adrenergic Receptor Protein breakdown Gs G Stimulatory Protein AC Adenylate Cylase ATP Adenosine Triphosphate cAMP Cyclic Adenosine Monophospate PKA Phosphokinase A Beta Agonist Classification Endogenous Beta Agonist OH HO NH2 HO · Name: Norepinephrine · Class: Phenethanolamine Catecholamine · Source: Neurotransmitter substance released at central and sypathetic nervous system nerve endings Circulates in the plasma at Moody et al., 2000 Mersmann, 1998 relatively high concentrations Endogenous Beta Agonist OH H HO N HO · Name: Epinephrine · Class: Phenethanolamine Catecholamine · Source: Synthesized in and secreted from the adrenal medulla Circulates at lower concentrations than norepinephrine Moody et al., 2000 Mersmann, 1998 Biosynthesized from norepinephrine Classification of Phenethanolamines What is a Phenethanolamine? Phenyl Ethanolamine All phenethanolamines have the Group Group same base structure indicated in green A OH Phenethanolamines differ in their B CH•CH •NH•R substituents at positions A, B, C, 2 and R indicated in orange C Beta Receptor Selectivity of Beta Agonists used as Metabolic Modifiers OH OH OH H H N N HO H N Ractopamine (b1) 2 N L•644,969 (b2) OH OH H H N N H N 2 HO Cimaterol (b ) Salbutamol (b ) 2 HO 2 N H O H OH N H Cl N N H N H2N Cl Clenbuterol (b2) O Zilpaterol (b2) Growth and Carcass Summary Growth Performance Control 68 kg 49 days 109 kg 147.7 kg feed Ractopamine Ractopamine effect 68 kg 45 days 109 kg • 4 days 129.1 kg feed • 18.6 kg feed Carcass Dressing Yield 82.45 kg 81.27 kg + 1.18 kg Boneless, Closely Trimmed Cuts 52.34 kg 49.69 kg + 2.65 kg Total Dissected Carcass Lean 47.42 kg 42.10 kg + 5.32 kg Note: Calculations based on 20 ppm Ractopamine treatment and equal slaughter weight basis Trials: Twenty trial summary, 6 trial summary, 4 trial summary Factors that influence response to treatment with phenethanolamines Factor Requirement Compounds Species Studied Greater response with Clenbuterol Pigs, Broilers, Rats Dietary Protein higher dietary protein BRL47672 Ractopamine Duration of Greater response Cimaterol Pigs, Cattle, Sheep during final finishing Clenbuterol Treatment phase L•644969 Ractopamine Dosage Differential effect on Ractopamine Pigs growth and leanness Age or Weight Greater response with Cimaterol Pigs, Cattle older, heavier animals Ractopamine Genetics Effective in both fat Cimaterol Pigs, Mice and lean genetics Ractopamine Moody et al., 2000 Nutrient Pool With Ractopamine Adipose Tissue Lipogenesis Lipolysis Decreased Increased Fat Deposition rate reduced by 6% Adapted from Bauman et al., 1982; Fed.