Lecture 3 - Metabolic role of amino acids Flashcards
Amino acids: major roles in metabolism
Metabolismfor ATP synthesisto maintain function-to maintain cell/organ/organism viability
What metabolism can do:
glucose, obesity, fasting /longevity
Contributions towards ATP
Different cells are different!
What is the substrate?
Is there a substrate preference?
What are pathway activities/reliance?
What is the oxygen availability?
Amino acids: more than a potential substrate
Each cell type has an upper limit for protein storage
(defined by its genetic profile)
e.g. skeletal muscle fiber vs erythrocyte
Excess amino acids are
degraded and used for ATP production or converted to fat or glycogen and stored (kidney, liver, mucosa)
Amino acid supplements in body building…
–> fat and glycogen (unless Δ in metabolic demand)
Amino acids for protein synthesis: cell specific
Genetic make-up controls protein expression profile (proteins control gene expression profile-downward causation)
Requirements for protein synthesis:
- Synthesis of the amino acids (availability)
- Appropriate amino acid conjugation
Availability of amino acids
10 amino acids can be synthesized (non-essential), 10 cannot/or in quantities that do not match organisms demand (essential)
Essential amino acids:
threonine, methionine, valine, leucine, isoleucine, lysine, arginine, phenylalanine, trypotophan, histidine
Also the non-essential amino acids are essential
- All or non function of amino acids in protein synthesis: if a single required amino acid is not available, the WHOLE protein cannot be synthesized!
- The protein synthesis and its magnitude is limited to the level of the lowest quantity of a specific amino acid
Synthesis of the nonessential amino acids
- Depends on the formation of the appropriate α-keto acid
Eg: pyruvic acid (glycolysis) keto acid precursor for alanine - Transamination
Transamination
amino radical transferred to the keto acid, the keto oxygen is transferred to amino radical donor
- is key for mitochondrial functioning
Transamination enzyme:
transaminases (ALAT, ASAT)
Key amino acidsin metabolism
Protein catabolism for ATP
Most amino acids used for ATP synthesis come not from protein catabolism but from surplus amino acids in diet
To make amino acids metabolically favorable, they need to
be deaminated!
Degradation for energy or storage as fat
Degradation begins with the process of deamination:
1. via transamination
2. via oxidative deamination
Generation of urea
- NH3
- ammonia is toxic
- if liver is dysfunctional = high levels of ammonia
Aquatic animals simply excrete ammonia
ammonotelic
Generation of urea: Where no/less water available:
conversion into less toxic products: urea (terrestrial vertebrates-ureotelic),
uric acid
(birds and reptiles-uricotelic)
Rapid removal from blood to form urea in the liver
All urea formed is synthesized in the liver (hepatic disease)
Urea cycle (urea renal excreted)
the main transport vehicle for nitrogen
Glutamine
Amino groups are transferred to α-ketoglutarate, forming glutamate, which in turn can accept more nitrogen forming glutamine. Glutamine: aminoradical donor + store house
Once de-aminated 3 valuable metabolic pathways exist
- TCA cycle
- Gluconeogenesis (liver and kidney, not muscle!)
- Acetyl-CoA –> fatty acid synthesis or ketogenesis (acetoacetic acid)
The central metabolic role of alanine
Alanine transaminated to pyruvate
Pyruvate oxidized to acetyl-CoA
Pyruvate carboxylated to oxalacetate
Aspartate + α-ketoglutarate<–> oxaloacetate + glutamate (AST or ASAT)
The central metabolic role of oxaloacetate
Condenses with acetyl-CoA to form citrate
Can be generated from cytoplasmic citrate (lyase)
Can be transported as malate
Transaminated to aspartate vs generated from aspartate
Aspartate + α-ketoglutarate <–> oxaloacetate + glutamate (AST or ASAT)
Amino acids as fuel substrates: plentiful, multiple entry points in TCA cycle
Ketogenic amino acids
Glucogenic amino acids
Entry points of glucogenic and ketogenic amino acids
Branched-chain amino acids
Every entry point stands in some relationship with an amino acid exchange or transaminase system!
Amino acids and indirect role for mitochondrial respiration:
- Malate/Aspartate shuttle
Aspartate + α-ketoglutarate <–> oxaloacetate + glutamate (AST or ASAT) and its relation to malate
Transport of reducing equivalents to mitochondria
More entry points than anticipatedmaintaining and modulating TCA cycle flux AND providing metabolites
Amino acid oxidation: oxygen sparing
- very efficient way to make ATP
Failure in protein metabolism
= Failure in mitochondria (and vice versa)
- proteins start to aggregate = disfunction = parkinsons
Neurodegenerative disease if mutation in malate/ aspartate shuttle
AA’s can control TCA cycle, How?
By providing keto and glycogenic amino acids as fule/substrates
(good substrate for ATP production)
Amino acids –> pyruvate –> glucose
- gluconeogenesis
- 2 organs only: liver and kidney!
AA’s are taken up in the mucosa –> liver and kidneys –> preserves glucose levels (via gluconeogenesis)
Protein: large energy store
- Gets to brain through plasma - Thus also maintains plasma levels
Protein metabolism: an underestimated and neglected metabolic role player?
Contribution as substrates
Intermediary metabolism: TCA cycle flux
Gluconeogenesis
Oxygen efficiency and ATP yield
Malate shuttle for transport of reducing equivalents in mitochondrial respiration
Problem: 1. “unseen” amino acids: difficulty of measuring (radioactive tracer), inhibition of enzymes, protein synthesis, ATP consumption
- Dont know how much ATP a cell actually uses –> would have to inhibit something and measure decline in ATP use
Problem 2: Intracellular vs extracellular (plasma amino acids)
- How proteins absorbed/ transported and then what happens intracellularly
(2 different processes)
AA’s can be rapidly degraded (and made available) in big amounts.
Obligatory protein degradation
- 0-30 g protein/day is degraded, deaminated and oxidized
- To prevent net loss: 75 g protein intake/day is recommended
- If one amino acid is missing in the diet, the others become unusable failure in protein synthesis
- diet (complete vs incomplete proteins)
High carb diet = high insulin levels = cell cant undergo protein degradation
Hormones that regulate protein metabolism
- Growth hormone
- Insulin
- Glucocorticoids
- Testosterone
- Thyroxine
Growth hormone:
increase in protein synthesis rate
Insulin
is required for protein synthesis (lack of insulin decreases protein synthesis to almost 0); accelerate amino acid transport/uptake; by providing glucose, it spares amino acids from oxidation
Glucocorticoids:
increase in [amino acid] plasma; breakdown of extrahepatic proteins; important for aminoacid drived gluconeogenesis and ketogenesis
Testosterone:
increased deposition of protein, especially contractile proteins in muscle
Thyroxine:
depending on substrate availability it contributes to protein degradation or protein synthesis
Glucocorticoids increase amino acid availability
Thyroxin: increase amino acid availability or protein synthesis depending on metabolite availability
4 Thinking points
Amino acids as substrates (fuel for the metabolic engine)
Amino acids in intermediary metabolism (oil in the metabolic engine)
Amino acids and the nitrogen waist issue
Intracellular availability under normal conditions
