Part 1.1 Flashcards
Why do PET scans work for cancer detection?
How does it work?
PET = Positron Emission Tomography
Cancer takes over glycolysis and up-regulates it for ATP production to fuel cancer growth and also uses PPP to produce ribose and NADPH
Method: 2’ OH replaced with F18 (radioactive, photo emitting) to form FDG (fluorodeoxyglucose) which can enter through GLUT and hexokinase phosphorylates but then cannot proceed to glycolysis and accumulates in cancerous cells
4 key proteins of insulin signaling pathway
PKB - protein kinase B
GLUT4 - in muscle and adipose
GSK3 - glycogen synthase kinase 3
PP1 - protein phosphatase 1
Insulin binding on:
Glycogen synthase and glycogen phosphorylase
Including allosteric effectors
Glycogenesis (on):
1) Insulin binds and cascade activates PKB
2) PKB activates PP1 and deactivates GSK3
3) PP1 activates glycogen synthase + Glc-6-P (allosteric activator)
4) PKB also signals movement of GLUT4 to membrane
Glycogenolysis (off):
1) Insulin binds and cascade activates PKB
2) PKB phos activates PP1
3) PP1 inactivates (dephos) PK (phosphorylase kinase) and glycogen phosphorylase
*allosteric inactivation by Glc, ATP and Glc-6-P
Overview of glucose de-novo utilizations
Glycogenesis (fed)
Glycogenolysis (fasted)
Gluconeogenesis (liver in fasted/starving)
Synthesis of ribose, fructose and oligosaccharides (ex. glycoproteins)
Glycogen storage weight percentages
Liver and muscle glycogen use during exercise
10% of liver, 1-2% of muscle
During exercise the live generates glucose from glycogen for all cell needs
In muscle glycogenolysis is just used to fuel muscles
Reducing end of glycogen or sugar
Non-reducing ends of glycogen
C1 with OH is a reducing sugar
Reducing end of glycogen consists of glucose monomer covalently attached to glycogenin
Non-reducing ends have a terminal glucose with a free OH on C4
*glycogen is degraded/extended from non-reducing ends
Branching occurs at C6
Formation of acetyl coA and TCA as a metabolic intersection
Formation of acetyl coA from FAs, AA (via pyruvate), Glucose
*nutrients converging towards acetyl-coA
Acetyl-coA proceeds to TCA under catabolic conditions
- extraction of electrons
Under anabolic conditions acetyl coA and krebs cycle products can be diverted go on to build various end products
- acetyl coA used for lipogenesis + cholesterogenesis
Glycogenesis pathway
1) glucose enters cell, glc –> Glc-6-P by hexokinase/glucokinase + ATP
2) Glc-6-P –> Glc-1-P by phosphoglucomutase (PGM)
3) Glc-1-P + UTP –> UDP-Glc + PP by UDP-glucose pyrophosphorylase
* ATP is used to make UTP via NDP kinase
4) UDP-glucose + glycogen primer –> glycogen-glycogenin by glycogen synthase (RLS)
5) Glucosyl transferase creates branches to form glycogen
NADPH uses
PPP oxidative phase
NADPH used for anabolism: lipogenesis, cholesterol genesis
Antioxidant defense: glutathione regeneration (GSSG –> 2 GSH), lysosomes and RBC
Produced via PPP oxidative phase
1) G6PD glucose-6-phos dehydrogenase + NADPH (RLS, inhibited by NADPH)
2) gluconolactase (no NADPH produced)
3) 6-phosphogluconate dehydrogennase –> ribulose-5-P + CO2 + NADPH
G6PDH deficiency
400 million people worldwide, 25% of people in tropics
Clinical manifestations following environmental/xenobiotic stressor (increased sensitivity to ROS)
The malarial parasite is destroyed by G6PDH DEFICIENT RBC (adaptation)
Action of Mg2+ in hexokinase/glucokinase
Mg2+ complexes with ATP so that the O on C6 can nucleophilic attack the gamma phosphate group on ATP
Without Mg2+ there is no reaction
Polysaccharide and oligosaccharide digestion enzymes
Salivary a-amylase –> pancreatic a-amylase –> maltase (SI) –> 2 a-D-glucose
Mechanism of action of amylase
Glycosylation:
1) Acidic AA (Glu/Asp) carboxyl attacks C1 position of glucose attached to amylose
2) The O-C1 attacks H on another Glu/Asp residue (Glucose now attached to first Glu/Asp
*Sum: Active site AA #1 catalyzes addition of glucose to enzyme
DeGlycosylation:
3) Acidic residue O- attacks H of water
4) OH of water attacks C1 on glucose and breaks covalent bond
5) Free glucose is released
*Sum: Active site AA #2 activates water to break bond btwn enzyme and shortened amylose/glucose
Enterocyte pathways to satisfy energy demands
- Enterocytes use a little glucose
- A-ketoglutarate via AA metabolism used for ATP production from Glu (from Gln, His, Arg, Pro)
- SCFA oxidation with fatty acyl coA synthase, CPT1 (RLS) and CACT
Conversion of Gln, His, Arg and Pro –> Glu
Reverse
Conversion of Glu –> a-ketoglutarate
Reverse
1) Gln + H2O –> Glu + NH4+ via glutaminase
2) Glu + NH4+ + ATP –> Gln + ADP + P via glutamine synthase
1) Glu + NAD+ –> NADH + NH4+ + a-ketoglut via glutamate dehydrogenase (liver)
2) a-ketoglut + NADPH + NH4+ –> Glu + NADP+ via glutamate dehydrogenase (liver)
SCFA entry into mitochondria
1) FA + coA + ATP –> Fatty acyl coA + AMP/PP via fatty acyl coA synthase
- crosses into intermembrane mitochondrial space
2) Fatty acyl coA + carnitine –> fatty acyl carnitine + coA via CPT1 (RLS)
3) Fatty acyl carnitine enters mitochondrial matrix via CACT (carnitine acylcarnitine translocase, anti-porter)
4) Fatty acyl carnitine + coA –> fatty acyl coA + carnitine via CPT2
Oral anti-diabetic drugs and mechanisms
Metformin - inhibition of hepatic glucose releaseand decreased glucose absorption
Glibenclamide (sulfonylurea) - inhibition of the ATP-sensitive K+ channels, which leads to depolarization of the cells and insulin secretion
GLP-1 incretin - increases insulin release, and decreases gastric emptying rate and appetite
Acarbose - slows enteral glucose absorption
Rosiglitazone (thiazolidinedione derivative) - binds PPAR nuclear receptors and improves insulin sensitivity
