glucose metabolism
DESCRIPTION
Glucose metabolism. Processes Glycolysis Glycogenolysis Gluconeogenesis Substrate level regulation Hormone level regulation. Carbohydrate metabolism. Glycolysis Breakdown of glucose to pyruvate Provides substrate for TCA cycle Gluco-/glyco-neogenesis Synthesis of glucose or glycogen - PowerPoint PPT PresentationTRANSCRIPT
Glucose metabolism
• Processes– Glycolysis– Glycogenolysis– Gluconeogenesis
• Substrate level regulation
• Hormone level regulation
Carbohydrate metabolism
• Glycolysis– Breakdown of glucose to pyruvate– Provides substrate for TCA cycle
• Gluco-/glyco-neogenesis– Synthesis of glucose or glycogen– Storage of excess substrate
• Regulatory mechanisms– Allosteric– Phosphorylation
Glycolysis
• Convert Glucose to Pyruvate– Yield 2 ATP + 2 NADH per glucose– Consume 2 ATP to form 2x glyceraldehyde
phosphate– Produce 2 ATP + 1 NADH per GAP
• Carefully controlled– 12 different enzyme-catalyzed steps– Limited by phosphofructokinase– Limited by substrate availability
Glycolysis/Gluconeogenesis
-D-Glucose-1P
-D-Glucose-6P
-D-Fructose-6P
-D-Fructose-1,6,P2
Glyceraldehyde-3P
Glycerate-1,3P2
Glycerate-3P
Phosphoenolpyruvate
Pyruvate
phosphoglucomutase
glucose-6-phosphate isomerase
6-phosphofructokinase
fructose-bisphosphate aldolase
fructose-1,6-bisphosphatase
Glycerate-2P
GAPDH
phosphoglycerate kinase
phosphoglycerate mutase
enolase
pyruvate kinase
Hexose importStarch/glycogen breakdown
Except for these steps, glycolysis happily runs backward. Backwards glycolysis is gluconeogenesis
hexokinase
D-Glucose
Glycolysis: phosphorylation
• ATP consuming– Glucose phosphorylation by hexokinase– Fructose phosphorylation by
phosphofructokinase
• Triose phosphate isomerase
Glycolysis: oxidation
• Pyruvate kinase– Transfer Pi to ADP– Driven by oxidative
potential of 2’ O
• Summary– Start C6H12O6
– End 2xC3H3O3
– Added 0xO– Lost 6xH– Gained 2xNADH, 2xATP
NADHATP
pyruvate kinase
GAPDH
phosphoglycerate kinase
Pyruvate
• Lactic Acid– Regenerates NAD+– Redox neutral
• Ethanol– Regenerates NAD+– Redox neutral
• Acetyl-CoA– Pyruvate import to mitocondria– ~15 more ATP per pyruvate
pyruvate2-Hydroxyethyl-
Thiamine diphosphate
S-acetyldihydro-lipoyllysine Acetyl-CoA
Carbohydrate Transport
• H+, pyruvate cotransporter
Halestrap & Price 1999
Major Facilitator SuperfamilyMonocarboxylate transporter
Competition between H+ driven transport to mitochondria and NADH/H+ driven conversion to lactate
Cytoplasmic NADH is also used to generate mitochondrial FADH2, coupling transport to ETC saturation “glycerol-3P shuttle”
Gluconeogenesis
• Regenerate glucose from metabolites– Mostly liver– Many glycolytic enzymes are reversible
• Special enzymes– Pyruvate carboxylase
• Generate 4-C oxaloacetate from 3-C pyruvate
– Phosphoenyl pyruvate carboxykinase• Swap carboxyl group for phosphate• Generates 3-C phosphoenolpyruvate from OA
– Fructose-1,6-bisphosphatase• Generates fructose-6-phosphate
Mitochondrial
Glycogen
• Glucose polysaccharide– Intracellular carbohydrate store– Easily converted to glucose
• Glycogenolysis– Phosphorylase generates glucose-1-P
from glycogen
• Glycogenesis– Glycogen synthase adds UDP-glucose-1-P
to glycogen
Substrate control of CHO metabolism
• Kinetic flux balance
• Competition for energy-related molecules– Oxaloacetate: endpoint of TCA– Pyruvate
• Allosteric regulation by energy-related molecules– ATP/AMP: PFK/PFP– F-1,6-BP: pyruvate kinase– Fatty acids
ADPATP
Metabolite feedback in glycolysis
G6p F6p F16p GAP
Gp2PEP
Pyr
Lac
AcCoA
NAD
NADH
ATP ADP
G3pG2p
PGI PFK ALD
GAPDH
PGKPGAMENO
PK
LDH(M)
PDH
NAD
NADH
NADH
ADP
ATP
Substrate competition
• Oxaloacetate– Oxa + AcCoA citrate– Oxa + GTP GDP + PEP
• Acetyl-CoA– Oxa + AcCoA citrate– AcCoA + HCO3 MalonylCoA fatty acids– Amino acid synthesis
Oxaloacetate Citrate
=
Phosphoenylpyruvate
Adenine nucleotides balance glucose breakdown
• PFK activity depends on ATP/AMP– Competitive binding to regulatory domain
• PFP activity depends on AMP/citrate
ATPAMPPFK PFP
Glycolysis
PFK Glycolysis ATP
AMP
PFP Glycolysis AMP
Phosphofructokinase
• Substrate cooperativity
• Fructose 1,6-bisphosphate
Mansour & Ahlfors, 1968
+cAMP
PFK activity
Change in slope of concentration-activity curve
Hormonal control of CHO metabolism
• Liver/periphery (liver/muscle)– Glucagon – glucose release– Insulin – glucose uptake
• System wide response– Distribution of receptors– Tissue specialization
• Effector systems– Glucose uptake– PFK/PFP balance
Systemic Regulation of Blood Sugar
• Pancreas– -cells:GlucoseATP--|KATP--| DepolarizationCa
insulin+GABA release– -cells:GABACl- --|glucagon
• Peripheral tissues– Insulin IRPI3KGLUT4 translocation glucose uptake– PI3KPKB--|GSK--|GS
• Liver– GlucagonGRGsACPKA--|GS
GlucagonGlycogenolysis(Liver)
Blood glucose
InsulinGlucose uptake, glycogenesis (muscle)
Glucagon
• Endocrine factor, Gs coupled receptor
• PLC, AC enhance glycogenolysis– Rapid secretion of glucose from liver
Jiang, G. et al. Am J Physiol Endocrinol Metab 284: E671-E678 2003;doi:10.1152/ajpendo.00492.2002
PLC AC
Tiedgen & Seitz, 1980
Insulin/Glucagon ratio
Hep
atic
cA
MP
Glucagon:Insulin
• Glucagon– Liver only– GPCR
• PLC• Adenylate cyclase
– Activates GP– Inhibits GS– Stimulates
gluconeogenesis
• Insulin– Most tissues– RTK
• PI-3K• PP1
– Activates GS– Inhibits GP– GLUT-4 translocation
Glucose storage(muscle)
Glucose distribution(liver)
Phospho-regulation of glycogenThe straight activity version
• PKA+GP via phosphorylase
kinase
-GS
-PP1 via G-subunit
• PKB+GS via GSK
+PP1 via G-subunit
•PP1+GS-GP
PKA PKB
PK
PP1-G
GS
PP1-G
GS
GP
PP1 PP1
GSK3
GlycogenSynthesis
GP
Activates
Inhibits
Phospho-regulation of glycogenThe phosphorylation story
• PKA+GP via phosphorylase
kinase
-GS
-PP1 via G-subunit
• PKB+GS via GSK
+PP1 via G-subunit
•PP1+GS-GP
PKA PKB
PK
PP1-G
GS
PP1-G
GS
GP
PP1 PP1
GSK3
GlycogenSynthesis
GP
Phos/Increase
Dephos/Decr
Active Inactive