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Annette Beck-SickingerBiochemie und Bioorganische Chemie

Institut für Biochemie

Brüderstr. 34/Raum 312, Tel. 9736900abeck-sickinger@uni-leipzig.de

Receptor Biochemistry and Signal Transduction

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Organisation

Lecture: Tuesday 8.30-10.00 Beck-Sickinger

Seminar: Mo 17-18.30 or Mo 8.30-10.00Introduction + 7 seminars April/May/JuneIsabelle Ziffert, M. Sc. Biochem/Victoria Behr, M Sc Biochem/

Lab Course: 2.4.2019 - 18.4.2019; 10:30-17hDr. Karin Mörl + PhD students

Exam: oral exam by arrangement: July-September

Seminar – Receptor Biochemistry 2019(1st Group Monday 8:30 – 10.00)

Date Topic Name

Mo 29.04.2019 Signaling Pathways and Signal Complexes

Mo 06.05.2019 GPCR – Structural Features

Mo 13.05.2019 Ligand Design

Mo 20.05.2019 Crosstalk – Transactivation

Mo 27.05.2019Receptor Internalization and Membrane Trafficking

Mo 03.06.2019 Cancer and Inflammation

Mo 17.06.2019 Doping / Drugs‐Biased‐Signaling

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Block Lecture

9. 4. 2019 – 4. 6. 2019 8:30-10:00 small lecture hall, Brü 34, floor 2

Script can be downloaded from: Campus onlinehttps://biochemie.biphaps.uni-leipzig.de/en/study/ Login: studentsPasswd: BCh18COnLine!!

01.04. - 02.04.2019: Brüderstr 34

Mo 08:30-10:00 BeckmHS, EGMo 10:15-11:45 BeckmHS, EGMo 15:15-16:45 BeckmHS, EGTu 08:30-10:00 KHBr, floor 2Tu 10:30-12:00 KHBr, floor 2

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Literature and used text books

Gerhard KraussBiochemistry of Signal Transduction and RegulationWiley-VCH, ISBN 3-527-30591-2

Donald Voet, Judith G. Voet, Charlotte W. PrattLehrbuch der BiochemieWiley-VCH, ISBN 3-527-30519-X

Alberts et al.Molekularbiologie der ZelleWiley-VCH, ISBN-10: 3-527-30492-4

Latest references and reviews

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1. Hormone, Transmitter, Cytokine2. Introduction to Signal Transduction3. Different Types of Receptors4. Methods to Study and Investigate Receptors5. Channels and Transporter6. Cell Adhesion Molecules7. Proteolytic Cleavage Signals

Receptor Biochemistry and Signal Transduction

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Hormone, Transmitter, Cytokine

Ernest Henry Starling(* 17. April 1866; † 2. Mai 1927)Engl. Physiologist,Introduced in 1905 the name „hormone“.Hormone (griech. ὁρμάω hormáō „to push, toactivate“).

He discovered that the gut releases a compound after HCl incubation, that stimulates the pancreas. He called thecompound „secretine“

Isolated: 1961: Jorpes/Mutt (Karolinska Institut, Stockholm) 1 g from 1 km intestineConfirmed by synthesis: 1967 M. Bodansky

secretine

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Hormone/Transmitter: today

Biochemical signalstransmit information between cellsintercellular within tissuebetween neuronal cells via synapsesvia gland/blood system

Accordingly, no difference between transmitter and hormone….

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Classification

• Hormone production and release• Chemical classes• Hormone function/endocrinology• Hormone receptors

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Endocrinology

Science, deals withendocrine cycles.Endocrinologist: medicaldoctor, involved in therapiesof pathologies.

Hormones regulate • Metabolism of carbohydrates and fat• Regulation of food intake• Regulation of sexual hormones• Regulation of bone metabolism• Anxiety and stress • thyrotrope cycles

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Hormone producing cells

• Gland cells of (pituitary gland, pineal gland, thyroid gland, adrenal gland, pancreas)

• Sexual glands (Theca- and Granulosa-cells in women and Leydig-cells in men)

• Nerve cells (Neurohormones, Transmitters)• Liver (Angiotensin-precurser)• Gastro-intestinal tract (GI)• Adipocytes

Responsible: Specific enzyme pattern of each cell

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Hormone producing cells

Hypothalamus and RH

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Pituitary GlandPituitary GlandAnterior lobe: LH/FSH, ACTH,Prolactin, GH, TSHPosterior lobe: oxytocin, vasopressinReleased from nerve terminals

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Regulate the metabolic activity of the body

Thyroid Glands

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Feedback Loops

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Pineal Gland and Melatonin

plasma urine

degradation

Parathyroid Gland

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Parathyroid hormone(PTH) • most important endocrine

regulator of calcium and phosphorus concentration in extracellular fluid

• opposite effect of calcitonin. • stimulates osteoclasts which

increases blood calcium levels.

• causes reabsorption of Ca2+

from kidneys so it is not excreted in the urine

• stimulates synthesis of calcitriol (hormone made in the kidney which the active form of Vitamin D which increases Ca2+ absorption from small intestine

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Adrenal Gland

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PancreasAcini: Digestive enzymesIslet of Langerhans: Hormones

They contain four types of cells-alpha,beta,delta and PP (pancreatic polypeptide) cells.The alpha cells secrete glucagon: increases the level of blood sugar. The beta cells secrete insulin: uptake of glucose.The delta cells secrete somatostatin. It inhibits the release of other.Pancreatic polypeptide inhibits food intake.

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Tissue derived hormonesNeuro hormones/neurotransmitters:

released from neuronesGut hormones: regulate food intakeHormones from kidney, heart, lung, etc.Cytokines released from leukocytesAdiopose tissue releases adipokines

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Chemical Classes of HormonesProtein- und Peptidhormone Neuropeptides of Hypothalamus

~ Release hormonesLH/FSH, TSH, ACTH, GH~ Somatostatin~ Agouti-related Peptid~ Neuropeptide Y~ Leptin~ Ghrelin

Glycoproteinhormones of pituitary gland:~ Follikelstimulating Hormone Follitropin (FSH)~ Luteinazing Hormon Luteotropin (LH)~ Thyreotropin (TSH)~ Adrenocorticotropin (ACTH)

additional hormones of the pituitary gland:~ Growth hormones: GH~ Prolactin~ Melanocyte stimulating hormone (MSH)~ Galanin~ Kisspeptin FSH

Leptin

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Neuropeptide der Neuro pituitary gland:~ Adiuretin (Vasopressin)~ Oxytocin

Hormone of the parathyroid gland~ Parathormon~ Calcitonin

Hormone of the heart~ Atrial-Natriuretic Peptide (ANP)

Peptide hormones of the liver~ Insulin-like growth factor (IGF)

Proteine hormone of gonades~ Inhibin und Aktivin

Vasopressin

IGF

Chemical Classes of Hormones

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• Hormone of the pancreas:~ Insulin~ Glucagon~ Somatostatin (SST)~ Pancreatic Polypeptide (PP)

• Peptide hormones of the GI~ Cholecystokinin (CCK)~ Secretin~ Gastrin~ Ghrelin~ Vasoactive intestinale Peptide (VIP)~ Gastro-inbitoric Peptide (GIP)~ Peptid Tyrosyl-Tyrosin (PYY)

Glucagon

Chemical Classes of Hormones

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Amino acid derivatives• Catecholamine

~ Adrenalin /Epinephrine~ Noradrenalin /Norepnephrine~ Dopamine

• Thyroxin (T4) and Triiodthyronin (T3)• Serotonin und MelatoninSteroidhormones• Mineralocorticoides – as Aldosteron• Glucocorticoides – as Cortisol• Estrogenes – as Estradiol• Gestagenea – as Progesteron• Androgenea – as TestosteronArachidonic acid derivatives (Eicosanoide)• Prostaglandine• Leukotriene• Thromboxane

Cortisol

Thyroxin

Serotonin

Thromboxan A2

Chemical Classes of Hormones

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Biosynthesis of Hormones

Protein biosynthesis (ribosomal) Signalpeptide for translocation to ER Posttranslational Modification

proteolytic cleavage (MSH)Disulfide bridges (Oxitocin, Insulin)Glycosylation (TSH)Sulfatation (CCK, gastrin)Lipidisation (Ghrelin)C-terminal Amidation (NPY, PP)

Secretion by vesicles

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continuously released

releasedafter signal

Continuous and regulated release

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Proopiomelanocortin

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Biosynthesis of Angiotensin

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Biosynthesis of Neuropeptide Y

pre-proNPY

Signalsequenz(28 aa)

NPY(36 aa)

C-flanking peptideof NPY (33 aa)

Signalpeptidase

proNPY

Prohormonconvertase (PC1/3, PC2)

Carboxypeptidase B-like Enzyme

Peptidylglycine--amidating-monooxygenase (PAM)

- NH2NPY

1 6936

1 36

1 39

YGKR

YGKR

YGKR

YG

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C-terminal AmidationC-terminal amidation of peptides: oxidative

Peptidylglycine--hydroxylating monooxidase (PHM)

PAL:peptidylamidoglycollate lyase

irreversible

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Biosynthesis of non-protein hormones

• Amino acid derivates– Decarboxylation of amino acids– Thyroid hormones (Tyr)– Catecholamine

• Steroid-Biosynthesis• Eicosanoid-Biosynthesis

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Amino acid derivatives

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Amino acid derivatives

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Thyroid Gland Hormones

• Uptake of iodid by sodium/iodid transporter (cotransport)• Thyreoperoxidase (TPO, Iodid-Peroxidase, or Iodid-

hydrogenperoxide-Oxidoreductase) catalyzes introductionof iodid

Iodid is oxidized to iodine, which immediately substitutes at tyrosine

Iodid is oxidized to iodine, which immediately substitutes at 3-I-tyrosine

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Thyroid Gland Hormones

Why Iodination?

90 °-angle of aromatic ringslead to uniquestructure

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Catecholamine