BIOC 2300 Lecture Notes - Lecture 24: Malate Dehydrogenase, Ketone Bodies, Malic Acid
3 May 2018
School
Department
Course
Professor
Integration of Metabolism
March 28-30, 2016
Cellular Locations of Major Pathways:
Compartmentation of glycolysis and gluconeogenesis
• Malate-aspartate shuttle for NADH involves oxaloacetate
o NAD+ is reduced to NADH in matrix when malate (as transport) is converted to
oxaloacetate aspartate
o Oxaloacetate is indirectly transported into the cytosol to enter gluconeogenesis
▪ Transport is necessary for most substrates to enter gluconeogenesis
▪ Oxaloacetate is converted by malate dehydrogenase in the mitochondrial
matric
▪ Malate is transported into cytosol
o Alcohol intoxication can lead to hypoglycemia
▪ Ethanol is metabolized in the cytosol to acetyl-CoA generates NADH
in cytosol
• Malate dehydrogenase is prevented from malate/NAD+
OAA/NADH
• Blood glucose levels drop = hypoglycemia
Regulation of Metabolic Pathways
• Maintenance of cellular homeostasis
o Regulation by energy levels
o Regulation to avoid build up = feedback inhibition, substrate activation,
feedforward…
o Regulation mostly through allosteric effectors and substrate availability
• Maintenance of homeostasis in organism
o Coordination in different tissues regarding energy and metabolite levels
o Regulation through hormonal signalling leading to changes in enzyme activity
through covalent modification
OVERALL METABOLIC HOMEOSTASIS
• Each tissue must receive sufficient energy
• Prevent build up of metabolites
• Xenobiotics must be degraded
• Must coordinate:
o Energy storage and metabolism
o Food intake and energy expenditure
o Metabolite levels in the blood
o Uptake and excretion of metabolites
*See characteristics of different energy substrates
• Fatty acids
• Glucose
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• Amino acids
Metabolic “goals in different metabolic states:
• Fed State
o Removes glucose from blood
o Stores energy for later
o Ex. Resting
• Post-absorptive
o Provides glucose to tissues that need glucose
o Provides energy to tissues to maintain glucose levels
o After food had been digested
• Fasting
o Same as postabsorptive
o Reduces glucose requirements as much as possible
• Exercise
o Provide energy to muscles
o Increase oxygen supply to muscle
Every tissue has a different metabolic profile:
• Blood: glucose and triacylglycerols
• Liver: glucose, ketone bodies, lipoproteins
• Brain: little energy storage = constantly needs it
• Muscle: lactate + amino acids (alanine), glycogen for activity
• Adipose tissue: fatty acids and glycerol **biggest energy stoarage (triacylglycerols are
most energy rich/ largest)
Organs are specialized for different functions
• Brain
o No energy storage
o No fatty acid oxidation
o Glucose is obligatory fuel
o No secretion of energy metabolites
o Ketone bodies used when present
o Even after long starvation, ketone bodies cover ~70% of energy – brain always
needs glucose
• Heart
o No energy storage
o Uses fatty acids or glucose
o No secretion of energy metabolites
o Ketones bodies used when present
• Adipose tissue
o Fed State
▪ Uptake of glucose and FA
▪ Synthesis of TG
▪ Goals:
• Removed glucose after a meal
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• Storage of energy for later
o Fasted State
▪ Lypolysis of TG
▪ Secretion of FA and glycerol (to liver)
▪ Goals:
• Provision of energy during fasting
• Skeletal Muscle
o Fed State
▪ Glucose uptake (storage as glycogen)
▪ Amino acid uptake protein synthesis
o Fasting
▪ Protein break (aa to liver)
▪ At rest: FA oxidation
▪ Ketone bodies used if present
o Active
▪ Glycogenolysis
▪ Anaerobic glycolysis
▪ Secretion of lactate
▪ FA oxidation with sufficient oxygen
o Goals:
▪ Removal of blood glucose after meal
▪ Storage of energy for activity (glycogen)
▪ Provision of glucogenic precursors
• Kidney
o Gets rid of nitrogen and water soluble metabolites
o Urea is synthesized in liver !
o Filters the urea in kidney
• Liver
o Fed:
▪ Glycogen synthesis and storage
▪ Glycolysis
▪ VLDL secretion
o Fasted:
▪ Glycogenolysis
▪ Gluconeogenesis
▪ Ketogenesis
▪ VLDL secretion (general homeostatic mechanism = cholesterol)
▪ Urea cycle (more excess ammonium)
Glucose use during Fast-Feed cycle:
• Right after meal, dietary glucose is used quickly (within hours) by many tissues
• The liver glycogen increases when dietary glucose declines for approximately 8 hours
(then decrease for 2 days)
• Gluconeogenesis increases as liver glycogen and dietary glucose have been used up
• The glucose use from the body as a whole then decreases (not as much will be needed
due to ketone bodies)
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Oaa/nadh: blood glucose levels drop = hypoglycemia. *see characteristics of different energy substrates: fatty acids, glucose, amino acids. Metabolic goals in different metabolic states: fed state, removes glucose from blood, stores energy for later, ex. Metabolic changes in different states are coordinated by different hormones: fed state: insulin, removed glucose from blood, store energy for later, postabsportive, fasting, exercise. Hormones convey short and long-range signals: can be polypeptides, aa derivatives, steroids, signalling through specific receptors, maintenance via homeostasis, respond to external stimuli, follow cyclic programs, signalling: bind receptor, mediate response, terminate signal, endocrine vs. paracrine vs. autocrine. Signal transduction: gene expression, enzyme modification, cytoskeletal rearrangement. Ionotrophic receptors (ion channels/ neurotransmitters: gpcr (>800; epinephrine, glucagon)** visual, taste, smell, rtk (insulin, growth factors)*, cytokine receptors (inflammatory molecules, nuclear hormones receptors (inside cell) Insulin, glucagon and catecholamines are important hormones for fuel metabolism. Hypoglycemia and hyperglycemia are balanced by glucagon and insulin.
