medical-notes/content/Biokemi/Metabolism/Aminosyrametabolism/Slides.md

---
föreläsare: Martin Lidell
tags:
  - biokemi
  - aminosyrametabolism
  - slides
date: 2025-12-08
---
# LPG001
Martin Lidell
Amino acid metabolism

## Lecture outline
 Amino acids – a short introduction
 How do we get access to amino acids?
 Biosynthesis of non-essential amino acids
 The origin of the a-amino group and the carbon skeleton
 Degradation of amino acids
 What happens with the amino group and the carbon skeleton?
 The urea cycle
 Transport of nitrogen to the liver (alanine/glutamine)
 Examples of some defects in amino acid metabolism

## Amino acids
Definition:
An amino acid is a simple organic 
compound containing both a carboxyl 
and an amino group
More than 500 different amino acids 
have been described in nature
Twenty a-amino acids (21 if including 
selenocysteine) are commonly found 
in mammalian proteins. These 
proteinogenic amino acids are the 
only amino acids that are coded for 
by DNA

## Amino acids – examples of some important non-proteinogenic amino acids
GABA (g-amino acid)
g-aminobutyric acid (GABA)
an inhibitory neurotransmitter
Ornithine and Citrulline
intermediates in the urea cycle
Ornithine (a-amino acid)
Citrulline (a-amino acid)

## Why are amino acids essential biomolecules? – some examples
Building blocks in proteins
Precursors of important biomolecules
(neurotransmitters, hormones, etc. etc.)
Dopamine Epinephrine
Source of energy
Acts as neurotransmitters (e.g. Glu and Gly)
Involved in acid-base homeostasis (Gln)
Transport ammonia in a nontoxic form (Gln and Ala)

## Overview of amino acid metabolism
Endogenous proteins
De novo synthesis of non-essential amino acids
Dietary proteins
Synthesis of other important biomolecules
Degradation
Amino group → Urea
Carbon skeleton → Ketone bodies, Glucose/glycogen, Energy, CO2 + H2O, Fatty acids
Refilling reactions
Amino acids
Urea cycle

## Digestion of dietary proteins in the gastrointestinal tract

## Amino acids, di- and tripeptides are absorbed by the enterocytes and released as amino acids into the blood
The absorbed di- and tripeptides are digested by peptidases into free amino acids that are released into the blood

## Intracellular degradation of endogenous proteins – released amino acids can be reused
Proteasomal degradation

## Biosynthesis of amino acids – the a-amino group and the carbon skeletons

## Biosynthesis of amino acids – the a-amino group
The a-amino group is most often derived from glutamate

## Biosynthesis of amino acids – the carbon skeletons

## Most microorganisms can synthesize all of the common proteinogenic amino acids

## Biosynthesis of amino acids in humans – essential and nonessential amino acids
Nonessential:
Alanine, Arginine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Tyrosine
Essential:
Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine

Humans cannot make the essential amino acids; they must be supplied in the diet
Some nonessential amino acids become essential under certain circumstances (“conditionally essential”)
e.g. arginine for fetus/neonate; tyrosine in PKU

## Biosynthesis of nonessential amino acids in humans
The carbon skeletons are derived from five precursors:
• 3-Phosphoglycerate
• Pyruvate
• a-Ketoglutarate
• Oxaloacetate
• Phenylalanine

## Formation of glutamate from a-ketoglutarate
Glutamate is primarily formed in transamination reactions catalyzed by different aminotransferases

## Aminotransferases / Transaminases
Enzymes transferring amino groups from a-amino acids to a-keto acids
a–amino acid-R1 + a–keto acid-R2 → a–keto acid-R1 + a–amino acid-R2
a-Ketoglutarate/Glutamate is the most common amino group acceptor/donor pair.
The reactions are reversible.
Essential for both synthesis and degradation of amino acids.

## ALT and AST – two important aminotransferases
Amino acids: Alanine, Aspartate, Glutamate
a-Keto acids: Pyruvate, Oxaloacetate, a-ketoglutarate

## Aminotransferases as indicators of tissue damage
• Intracellular enzymes
• Elevated plasma levels indicate cell damage
• ALT mostly in liver
• AST in liver, heart, skeletal muscle, kidney

## A second route of synthesis of glutamate from a-ketoglutarate
Glutamate dehydrogenase (mitochondrial, liver-specific)

## Arginine and proline – synthesized from glutamate
Arginine → part of urea cycle

## Glutamine and asparagine – formed by amidation
Enzymes: glutamine synthetase, asparagine synthetase

## Tyrosine – synthesized from phenylalanine
Reaction:
Phenylalanine + O2 + NADPH + H+ → Tyrosine + NADP+ + H2O

## Phenylketonuria (PKU)
Accumulation of phenylalanine, phenylpyruvate, phenyllactate, phenylacetate
Deficiency of tyrosine and metabolites
Autosomal recessive (PAH gene)
Hundreds of mutations
Insufficient phenylalanine hydroxylase activity

## PKU symptoms
Intellectual disability, delayed development, seizures, musty odor, fair skin/blue eyes
Treatment: dietary restriction, amino acid mix w/o Phe, tyrosine becomes essential, sapropterin may help

## “PKU-provet” – newborn screening since 1965
Blood sample after 48 hours
Purpose: detect treatable congenital diseases early

## Diseases included today (25 total)
Endocrine diseases (2)
Fatty acid metabolism defects (3)
Carnitine system defects (4)
Organic acidurias (6)
Urea cycle defects (3)
Amino acid metabolism defects (4)
Other metabolic diseases (2)
SCID

## Summary of part 1
(Amino acids important, sources, essential vs nonessential, aminotransferases, PKU)

## Excess amino acids cannot be stored
Amino acids not needed → degraded to intermediates that enter central metabolism

## How are amino acids degraded?
• Remove a-amino group
• Carbon skeleton becomes pyruvate, TCA intermediates, acetyl-CoA, acetoacetyl-CoA
Occurs primarily in liver; skeletal muscle degrades branched-chain amino acids

## Challenge: ammonia toxicity
Solution: liver → urea cycle  
Other tissues → transport as glutamine/alanine

## Glutamate as intermediate toward urea

## a-amino groups transfer to a-ketoglutarate → glutamate (ALT/AST)

## Oxidative deamination of glutamate
Glutamate dehydrogenase (liver mitochondrial matrix)

## Serine and threonine can be directly deaminated (dehydratases)

## Side-chain nitrogen of glutamine and asparagine – release ammonia and form glutamate

## Ammonia is toxic to CNS
Urea cycle detoxifies ammonia
Only active in liver

## Urea cycle
Carbamoyl phosphate synthetase I  
Ornithine transcarbamoylase  
Argininosuccinate synthetase  
Argininosuccinate lyase  
Arginase  
Urea contains 2 amino groups: one from NH4+, one from aspartate.  
Carbon from HCO3–

## Why is ammonia toxic? (theory)
Glutamine synthetase in astrocytes → glutamine accumulation → osmotic swelling → edema

## Regulation of urea cycle
N-acetylglutamate activates CPS I  
High glutamate + arginine → more N-acetylglutamate

## Defects in urea cycle – example: argininosuccinate lyase deficiency
Autosomal recessive  
Symptoms: hyperammonemia, irregular breathing, hypotonia, vomiting, alkalosis, brain swelling, seizures  
Treatment: glucose infusion, drugs promoting nitrogen excretion, dialysis, low-protein diet, liver transplant

## Drug treatment: arginine and phenylbutyrate

## Nitrogen transport from extrahepatic tissues
Extrahepatic tissues lack urea cycle  
Transport forms: glutamine and alanine  
Muscle uses BCAA

## Glutamine and alanine – nitrogen carriers

## Glucose-alanine cycle

## Where do carbon skeletons end up?

## Seven end-products of amino acid carbon skeleton degradation

## Citric acid cycle – source of building blocks
Cycle must be refilled (anaplerosis)

## Anaplerotic reactions
Pyruvate, amino acid skeletons refill TCA

## Glucogenic vs ketogenic amino acids
Glucogenic → pyruvate or TCA intermediates → glucose  
Ketogenic → acetyl-CoA or acetoacetyl-CoA → ketone bodies  
13 glucogenic  
5 mixed (Phe, Iso, Thr, Trp, Tyr)  
2 ketogenic only (Lys, Leu)

## Oxaloacetate as entry point for Asp/Asn

## a-Ketoglutarate as entry point for several amino acids
Glutamate → a-ketoglutarate (via GDH)

## Degradation pathways generating acetyl-CoA

## Degradation of phenylalanine and tyrosine

## Degradation of branched-chain amino acids
Occurs mainly in skeletal muscle

## Maple syrup urine disease (MSUD)
Autosomal recessive  
Defect in branched-chain a-keto acid dehydrogenase complex  
Accumulation of Leu, Iso, Val and their keto acids  
Symptoms: poor feeding, vomiting, low energy, abnormal movements, delayed development; severe cases seizures/coma  
Treatment: protein-restricted diet lacking Leu/Iso/Val; controlled supplementation

## Summary of part 2
• Amino acid degradation → ammonia → toxic  
• Glutamate central  
• Liver → only site of urea production  
• Extrahepatic tissues use glutamine/alanine  
• Carbon skeletons used for refilling, glucose, ketone bodies, fatty acids, energy

## Some important enzymes
ALT  
AST  
Glutamate dehydrogenase  
Glutamine synthetase  
Glutaminase  
Phenylalanine hydroxylase  
Carbamoyl phosphate synthetase I

## Läsanvisningar
Biochemistry (Berg et al.)  
Chapter 23: 701–703, 708–731  
Chapter 25: 766–790  
Instuderingsfrågor på Canvas  
Amino acid metabolism