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UIC PCOL 425 - Lecture 58

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ACTH Adrenomedullin ß-Amyloid(1-40) Anaphylatoxins Angiotensin II Angiotensin(1-7) Atrial Natriuretic Peptide BAM-12P, 18P & 22P Bombesin Bradykinin Brain Natriuretic Peptides Buccalin Bursin C-Type Natriuretic Peptide Caerulein Calcitonin Calcitonin Gene-RelatedPeptide Cardiodilatin Carnosine CASH (Cortical Androgen- Stimulating Hormone) Casomorphins Cerebellin Cholecystokinin Chromostatin CLIP Contraceptive Tetrapeptide Corticotropin Inhibiting Peptide Corticostatin Corticotropin ReleasingFactor Cytokines Delta Sleep-Inducing Peptide Dermorphin Dermaseptin Diabetes-Associated Peptide Diazepam Binding Inhibitor Dynorphins ß-Endorphin Endothelins Met-Enkephalin Leu-Enkephalin Epidermal Mitosis Inhibiting Peptide Erythropoietin Follicle Stimulating Hormone Galanin Gastric Inhibitory Polypeptide Gastrin Gastrin-Releasing Peptide a-Gliadorphin Granuliberin-R Glucagon Glucagon-Like Peptide Growth Factors Growth Hormone Growth Hormone- ReleasingHormone Guanylin Inhibin Insulin Interleukins Kallidin Kyotorphin a & ß-Lactorphin Leucokinins Lipotropin Luteinizing Hormone (LH) LH-Releasing Hormone Magainins Mastoparan Melanin-Concentrating Hormone a-Melanocyte Stimulating Hormone Melanostatin Morphine Modulating Neuropeptide Motilin a-Neoendorphin ß-Neoendorphin Neurokinin A Neurokinin B Neuromedin N Neuropeptide Y Neuropeptide P ß-Neuroprotectin Neurotensin Neutrophil Defensins Orexins Oxytocin PACAP (Pituitary Adenylate Cyclase Activating Peptide) Pancreastatin Pancreatic Polypeptide Parathyroid Hormone Peptide Histidine Isoleucine Peptide YY Prolactin Proctolin Rigin Secretin Somatostatin Substance P Systemin Thymosin Thyrotropin Thyrotropin Releasing Hormone Tuftsin Urocortin Uroguanylin Vasopressin (ADH) VIP (Vasoactive Intestinal Peptide) PPeptides and Peptidases as Targetsesfptides and Peptidases as Targets fofor Therapeutic Interventionr Theapeutic Intervention DDr. R.A. Skidgelr. R.A. Skidgel Biologically Active Peptidesically Active PeptidesGENERAL PRINCIPLES OF PEPTIDE METABOLISM 1. A Given Peptide Can be Cleaved by More Than One Peptidase2. A GIVEN PEPTIDASE CAN HYDROLYZE A VARIETY OF PEPTIDES. It is a common misconception that peptidases are peptide-specific, i.e., they hydrolyze only one particular peptide. This notion is perpetuated by the names given to some of the enzymes (e.g., Angiotensin I Converting Enzyme, Enkephalinase, Enkephalin Convertase, Anaphylatoxin Inactivator, etc.). In fact, peptidases are peptide-bond specific and can potentially cleave many different peptides. EXAMPLE 1: ANGIOTENSIN I CONVERTING ENZYMEEXAMPLE 2: NEUTRAL ENDOPEPTIDASE 24.11 3. The Function(S) Of A Peptidase Will Depend On Its Localization And The Peptide Hormones Available To It In That Location In A Particular Physiological Or Pathological Situation. POTENTIAL FUNCTIONS OF NEUTRAL ENDOPEPTIDASE 24.11 (NEPRILYSIN; NEP) Site Peptide Substrate Function Lung Substance P Control Secretion, Cough, Bronchoconstriction Kidney ANF, Bradykinin Regulate Salt and Water Balance Brain Enkephalins Alter Pain Perception Neutrophils Chemotactic Peptides Regulate ChemotaxisScheme of Peptide Hormone Processing & MetabolismScheme of Peptide Hormone Processing & MetabolismProhormoneReceptor 1Peptidase(s)InactiveFragmentsReceptor 2+ +orRK RREndoprotease-Gly-COOHActive Peptideor-CONH2Carboxypeptidase(Prohormone Convertases)PAMPeptide hormones are synthesized as larger prohormones. In most cases (e.g., neuro- and endocrine peptides), theprohormone is cleaved at paired basic residues (R-K, R-R, K-K, K-R) by an endoprotease (prohormone convertase) to release a peptide containing extra C-terminal Arg or Lys residues which are then removed by acarboxypeptidase to generate the active peptide. In some cases, removal of a C-terminal basic residue(s) exposes a C-terminal Gly residue, which is converted by peptide a-amidating monooxygenase (PAM) in a two-step reaction to a C-terminal amide group. After interaction with a specific receptor, the peptide is cleaved by peptidases into inactive fragments or, in certain cases, into a fragment which may have altered activity and receptor specificity.B2B1ACEAI (Inactive)AIIFRBKPFBKPBKP(Inactive)(Active)B2ActivateInactivateModulateExamples: Angiotensin (AII) and Bradykinin (BK)XPage 2 of 15 GENERATION OF MULTIPLE PROTEINS FROM ONE GENE VIA RNA SPLICING This scheme illustrates the transcription of DNA into a primary RNA transcript that containsintervening sequences (introns) which are not present in the mature RNA. The primary RNAtranscript is spliced to remove the introns giving the mature RNA containing only exons. Themature RNA contains untranslated regions at both ends and a contiguous sequence in themiddle which is translated into protein. In some cases, alternative splicing of the RNA can leadto more than one type of mRNA resulting in the synthesis of multiple proteins from one gene.STRATEGIES FOR DEVELOPING THERAPEUTIC AGENTS I. MIMIC THE ACTION OF A PEPTIDE HORMONE A. Administer the Peptide Ž ADVANTAGES: 1. Highly Potent Agents (Active at 10-15M to 10-7M) 2. Wide Variety of Biological Activities 3. Readily Synthesized Ž DISADVANTAGES: 1. Very Rapidly Degraded by Peptidases 2. Excreted by Kidney 3. Short Duration of Action (seconds to minutes) 4. Poorly Absorbed from GI Tract 5. Inconvenient Administration (e.g., i.v., intra-nasal) 6. Do Not Cross Blood-Brain Barrier 7. Expensive to Synthesize B. Stimulate Endogenous Synthesis of the Peptide M Advantage: Level of the peptide can be specifically increased at its normal site of action M Disadvantage: Control of synthesis of most peptide hormones is poorly understood C. Block the Degradation by Peptidase(s) M Advantages: 1. Level of the peptide can be specifically increased at its normal site(s) of action. 2. Peptidase inhibitors can be synthesized with good stability and bioavailability. M Disadvantages: 1. Blocking one peptidase may interfere with the metabolism of more than one peptide. 2. Inhibition of more than one peptidase may be needed to block the degradation of a peptide. 3.


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UIC PCOL 425 - Lecture 58

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