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+---
+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