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1 BIOCHEMIE Des Stoffwechsels BIOCHEMIE des Stoffwechsels Speicherkohlenhydrate Glykogenabbau (772.113) Glycogensynthese Regulation und Integration des Glycogenstoffwechsels 10. Einheit Signaltransduktion (Insulin, Glucagon, Glycogen Stoffwechsel Adrenalin) Höhere Organismen bilden GLUCANE als Brennstoffspeicher (Depot- Polysaccharide). Der Vorteil dieser Glucane liegt in ihrer raschen Speicherkohlenhydrate Mobilisierbarkeit und in der Tatsache, dass durch die Polymerisierung der osmotische Druck in der Zelle drastisch gesenkt wird. Der osmotische Druck hängt nicht vom Molekulargewicht sondern von der Stoffmenge ab. Pflanzen: Stärke (Amylose, Amylopectin) Tiere: Glycogen Stärke dient als Energie- bzw. Nährstoffreserve für Pflanzen und als wichtige Kohlenhydratquelle für tierische Organismen. Stärke kommt im Cytosol der Pflanzenzelle in Form unlöslicher Granula vor und besteht aus -Amylose und Amylopectin. -Amylose (20-30%) ist ein lineares Polymer aus einigen tausend Amylopectin (70-80%) ist ein Polymer aus (14)-glycosidisch Glucose-Einheiten, die (14)-glycosidisch miteinander miteinander verknüpften Glucoseeinheiten mit (16)- verknüpft sind. Unregelmäßig, helical geknäuelte Aggregation. Verzweigungen an jeder 24.- 30. Glucoseeinheit. Zählt mit bis zu 106-Glucosemolekülen zu den größten Makromolekülen in der Links-gängige H OH Natur. Helix OH H O H HO H O HO H H HO OH H OH HO H H O H OH H O -1,4-Bindung zwischen H H O zwei Glucose-Einheiten HO H (16)- H2C H H OH O glycosidische HO H O HO H Bindung H OH -glycosidische Bindungen neigen generell zu helicalen Schematische Darstellung der verästelten H OH Struktur des Amylopectins Polymeren, während -glycosidische Bindungen (z.B. (Verzweigungsstellen sind rot). Realität: Cellulose) gerade Stränge (Strukturfasern) bilden. Abstand zwischen zwei Verzweigungsstellen: 24-30 Glucoseeinheiten 1 Der Mensch benötigt 160 + 20 g an Glucose pro Tag (75% davon Verdauung von Stärke und tierischem Glycogen: benötigt das Gehirn). Diverse Körperflüssigkeiten (z.B. Blut) Mundbereich: -Amylase (Endoglucosidase) im Speichel spaltet transportieren etwa 20 g und 180 - 200 g werden in Form von lineare (14)-Bindungen, jedoch nicht solche, die an Glycogen gespeichert. Fazit: Der Körpervorrat reicht nicht viel mehr Verzweigungspunkten liegen. als für einen Tag! Magenbereich: -Amylase wird durch Säure inaktiviert. Die Prinzipiell gibt es drei mögliche Wege den Glucosebedarf zu decken: durchschnittliche Kettenlänge ist inzwischen von einigen 1000 auf durchschnittlich 8 reduziert. (A) NAHRUNG (z.B. Verdau von Stärkeprodukten oder tierischem Glycogen). Sehr effektiver, fast 100%iger Dünndarm: -Amylase des Pankreas (homolog der -Amylase der Abbau, jedoch nicht kontrolliert. Speicheldrüsen) bildet Gemisch aus (14)-verknüpfter Maltose (Disaccharid) und Maltotriose (Trisaccharid). Außerdem entstehen (B) GLYCOGENABBAU: unterliegt strenger Kontrolle Dextrine (Oligosaccharide) mit (16)-Verzweigungen. Weitere (C) GLUCONEOGENESE von Glucose aus Enzyme im Bürstensaum des Darmepithels sind -Glucosidase, Nichtkohlenhydraten (Lactat, Aminosäuren, Glycerin usw.): -Dextrinase und schließlich die Disaccharid-hydrolysierenden unterliegt strikter Regulation (siehe Einheit 9). Enzyme Saccharase, Maltase oder Lactase. -(14)-Glucosidase -(14)-Gucosidase -Amylase Glycogen: (1 4)-verknüptes Glucan (Exoglucosidase) spaltet (1 6)-Verzweigung im Abstand von 8-12 Resten endständige Glucosereste von Oligosacchariden ab. -Dextrinase (-(16)- Glucosidase; debranching (16)-Verknüpfung enzyme): hydrolysiert (16)- Reduzierendes Ende Nicht- und (14)-Verknüpfungen. reduzierende -(16)-Glucosidase Enden Saccharase (Invertase) spaltet Saccharose in Glucose und Verzweigungs (14)-Verknüpfung Fructose. punkt Maltase spaltet Maltose und Linksgängige Helix mit 6,5 Glucoseeinheiten pro Windung Lactase spaltet Lactose. Lokalisation im Cytoplasma. Granulas haben einen Durchmesser von etwa 10 bis 40 nm und ein Molekulargewicht von 6 106 bis 1600 106 Da. Ihr Massenanteil in Muskelzellen beträgt etwa 1 - 2 %, in Leberzellen hingegen bis zu 10%. Aufgrund der größeren Masse enthält die Skelettmuskulatur aber absolut mehr Glycogen. Die Granulas enthalten Glycogen und Enzyme des Abbaus, der Synthese und der Regulation des Glycogenstoffwechsels und z. T. auch der Glycolyse. Glycogen- Granula Leberzelle 2 Prozent (%) Glycogengehalt Während körperlicher Aktivitäten, stammt der Glycogen ist der wichtigste kurz- bis mittelfristige 100 Energiespeicher. Synthese und Abbau sind streng kontrolliert. Für Großteil der für die ATP- Geringe körperliche Säugetiere ist Glycogen in der Regulation des Blutglucose- Synthese notwendigen Aktivitäten Glucose aus dem Glycogen. Spiegels und als Glucosereservoir für anstrengende Muskelarbeit extrem bedeutend. Während körperlicher Moderate Aktivität wird nur ein 50 körperliche Fett kommt im Körper zwar in größeren Mengen vor als Aktivität geringer Anteil von Glucose Glycogen, kann jedoch nicht so schnell mobilisiert werden. Starke durch Gluconeogenese körperliche Fettsäuren können nicht anaerob metabolisiert werden. nachgeliefert. Aktivität Tiere können Fettsäuren nicht in Glucosevorstufen verwandeln. Der Glycogenabbau hängt Der Fettstoffwechsel kann den lebensnotwendigen Glucosespiegel von der Intensität der 0 im Blut nicht aufrechterhalten (siehe auch Einheit 9, Tätigkeit ab. 30 60 90 Gluconeogenese). Belastung in Minuten Gehalt an Glycogen im Muskel (g Glycogen pro kg Muskel) Nach 2 Stunden Speicherkohlenhydrate Effiziente Regenerierung 20 des durch körperliche körperlicher Tätigkeit Glykogenabbau Aktivitäten geplünderten Glycogen-Pools erfolgt 15 Kohlenhydrat- innerhalb eines Tages nur reiche Nahrung durch Kohlenhydrat- 10 reiche Nahrung! Regenerierung ohne Nahrungszufuhr Protein und fettreiche Nahrung regenerieren den 5 Fett- und Glycogenspiegel im Protein- Muskel nur sehr langsam. Diet 0 01020 30 40 Regenerierung des Glycogens in Stunden Muskel: Glycogen Glucose-1-P Glucose-6-P Glycogen-Abbau 1. Reaktion: Glycogen-Phosphorylase Glycolyse Phosphorolyse von Glycogen zu Glucose-1-phosphat. Leber: Glycogen Glucose-1-P Glucose-6-P Phosphorolyse bedeutet Bindungsspaltung durch Substitution mit Glucose Blut einer Phosphatgruppe Der letzte Schritt in der Leber wird durch das Enzym Glycogenn + Pi Glycogenn-1 + Glucose-1-phosphat Glucose-6-phosphatase katalysiert, das in den Muskeln fehlt (siehe Einheit 9). Freisetzung der Glucose von den nichtreduzierenden Enden (Enden ohne C(1)-OH-Gruppe) der Glucan-Kette. Freisetzung von Glucoseeinheiten, die wenigstens 5 Einheiten von der nächsten 3 Enzyme: Verzweigung entfernt liegen. Glycogen-Phosphorylase (oder Phosphorylase) Cofaktor: Pyridoxalphosphat Glycogen-debranching enzyme Homodimer: Pro Untereinheit 842 Reste (97 kDa). Glucosephosphat-Mutase Schrittmacher-Reaktion des Glycogen-Abbaus. Regulation durch allosterische WW, Substrat-Cyclus und kovalente Modifikation. 3 Nichtreduzierendes Ende Glycogen bildet linksgängige Schematische Helix in den nicht- Darstellung der verzweigten Regionen (6,5 verzweigten Glucosereste pro Windung). Struktur von Das Enzym Phosphorylase Glycogen. bindet dieses Motiv an der sog. „Glycogen- Ver- Reduzierendes speicherstelle“, einem 3 nm zweigungs- Ende punkt langen Spalt, der 4-5 Zuckerreste aufnehmen kann und diesselbe Krümmung wie die Glycogenhelix hat. Das Molekül besitzt unabhängig von seiner Größe nur ein einziges Sobald (16) reduzierendes Ende! Funktion der starken Verzweigung des Verzweigungen auftreten, Glycogens: Rascher Abbau des Glycogens durch gleichzeitige dissoziiert die Phosphorylase Freisetzung der Glucose an den Verzweigungsenden! ab. Wozu benötigt nun die Phosphorylase den Cofaktor Phosphorylase Pyridoxalphosphat? Pyridoxalphosphat kann vom menschlichen Körper nicht synthetisiert werden. Als Vitamin B6 wird es in Form von Turm Pyridoxin aufgenommen und im Körper zu Pyridoxalphosphat umgewandelt: CH2OH OH O- C Glycogen- Allosterisches OH -O Speicherstelle HO P OH Zentrum O O N-terminale Kontakzone N CH3 Glycogenbindungs- N CH3 subdomäne Pyridoxin Pyridoxal-5-phosphat (Vitamin B ) C-terminale 6 Katalytisches Zentrum Domäne Pyridoxalphosphat ist auch Cofaktor in Aminotransferasen (hat dort Pyridoxalphosphat-Bindungsstelle jedoch andere Funktionalität). O H Die Vitamine werden aus der Nahrung aufgenommen. Vitamine B Der Cofaktor sind wasserlöslich! Bereits besprochene Vitamine sind in rot C CN dargestellt: H Pyridoxalphosphat ist im CH2 aktiven Zentrum der Vitamin Cofaktor CH2 Phosphorylase über eine Thiamin (Vitamin B1) Thiaminpyrophosphat Schiff-Base kovalent Riboflavin (Vitamin B )FAD Lysin CH2 2 gebunden. + Niacin (Vitamin B3) NAD CH2 Pantothenat (Vitamin B ) Coenzym A N 5 Pyridoxin (Vitamin B6) Pyridoxalphosphat (siehe O- CH Glykogen- und Aminosäurestoffwechsel) -O P OH O Vitamin B12 Cobalamin O (Fettsäurestoffwechsel) N CH3 4 OH Pyridoxalphosphat ist ein wichtiger Cofaktor der Phosphorylase H Im ersten Schritt gibt und von Aminotransferasen (siehe Einheit 12). Die Funktionalität in H O Orthophosphat ein Proton an diesen Enzymsystemen ist aber komplett unterschiedlich. HO den 4-O der verbleibenden OH HO H H Abspaltung der Glucose am H OH Glycogenkette ab und erhält H O nichtreduzierenden Ende unter H O gleichzeitig ein Proton von der HO Rest HO H Beibehaltung der Phosphatgruppe des H OH Konfiguration, d.h. sowohl H Pyridoxalphosphats. H O Rest freigesetztes Glucose-1- O - H O Die Phosphatgruppe des phosphat als auch Glycogen P - O O Pyridoxalphosphats wirkt als -O haben am C-1 -Konfiguration. P - - O Protonendonor und in weiterer O Die Abspaltung erfolgt unter
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