Annette Beck-Sickinger Biochemie und Bioorganische Chemie ... fileRezBC~ST1 -1 Annette...
Transcript of Annette Beck-Sickinger Biochemie und Bioorganische Chemie ... fileRezBC~ST1 -1 Annette...
RezBC~ST1 - 1
Annette Beck-SickingerBiochemie und Bioorganische Chemie
Institut für Biochemie
Brüderstr. 34/Raum 312, Tel. [email protected]
Receptor Biochemistry and Signal Transduction
RezBC~ST1 - 2
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
RezBC~ST1 - 4
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
RezBC~ST1 - 5
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
RezBC~ST1 - 6
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
RezBC~ST1 - 7
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
RezBC~ST1 - 8
Hormone/Transmitter: today
Biochemical signalstransmit information between cellsintercellular within tissuebetween neuronal cells via synapsesvia gland/blood system
Accordingly, no difference between transmitter and hormone….
RezBC~ST1 - 9
Classification
• Hormone production and release• Chemical classes• Hormone function/endocrinology• Hormone receptors
RezBC~ST1 - 10
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
RezBC~ST1 - 11
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
RezBC~ST1 - 12
Hormone producing cells
Hypothalamus and RH
RezBC~ST1 - 13
RezBC~ST1 - 14
Pituitary GlandPituitary GlandAnterior lobe: LH/FSH, ACTH,Prolactin, GH, TSHPosterior lobe: oxytocin, vasopressinReleased from nerve terminals
RezBC~ST1 - 15
Regulate the metabolic activity of the body
Thyroid Glands
RezBC~ST1 - 16
Feedback Loops
RezBC~ST1 - 17RezBC~ST1 - 17
Pineal Gland and Melatonin
plasma urine
degradation
Parathyroid Gland
RezBC~ST1 - 18
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
RezBC~ST1 - 19RezBC~ST1 - 19RezBC~ST1 - 19
Adrenal Gland
RezBC~ST1 - 20RezBC~ST1 - 20RezBC~ST1 - 20
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.
RezBC~ST1 - 21RezBC~ST1 - 21RezBC~ST1 - 21
Tissue derived hormonesNeuro hormones/neurotransmitters:
released from neuronesGut hormones: regulate food intakeHormones from kidney, heart, lung, etc.Cytokines released from leukocytesAdiopose tissue releases adipokines
RezBC~ST1 - 22
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
RezBC~ST1 - 23
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
RezBC~ST1 - 24
• 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
RezBC~ST1 - 25
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
RezBC~ST1 - 26
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
RezBC~ST1 - 27
RezBC~ST1 - 28
continuously released
releasedafter signal
Continuous and regulated release
RezBC~ST1 - 29
Proopiomelanocortin
RezBC~ST1 - 30
Biosynthesis of Angiotensin
RezBC~ST1 - 31
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
RezBC~ST1 - 32
C-terminal AmidationC-terminal amidation of peptides: oxidative
Peptidylglycine--hydroxylating monooxidase (PHM)
PAL:peptidylamidoglycollate lyase
irreversible
RezBC~ST1 - 33
Biosynthesis of non-protein hormones
• Amino acid derivates– Decarboxylation of amino acids– Thyroid hormones (Tyr)– Catecholamine
• Steroid-Biosynthesis• Eicosanoid-Biosynthesis
RezBC~ST1 - 34
Amino acid derivatives
RezBC~ST1 - 35
Amino acid derivatives
RezBC~ST1 - 36
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
RezBC~ST1 - 37
Thyroid Gland Hormones
Why Iodination?
90 °-angle of aromatic ringslead to uniquestructure
RezBC~ST1 - 38
Catecholamine