L13 - Metabolic processes of the renal cortex and medulla Flashcards
Renal fuel metabolism varies with:
- Normal fed state
- Metabolic acidosis
- Fasting
N-compounds in urine (with daily amt)
(unit is g/day)
1) Urea (12-24)
2) Creatinine (1.0-1.8)
3) Uric Acid (0.2-0.8)
4) NH4+ (0.2-1.0; as high as 10 in acidosis)
Glutaminase
Renal enzyme that catalyzes:
Glutamine + H2O –> Glutamate + NH4+
Glutamine synthetase
Renal enzyme that catalyse:
Glutamate + NH4+ –> Glutamine
(ATP converted to ADP + Pi at this process)
Synthesis & Degradation of Glutamine
Glutamate dehydrogenase
Renal enzyme that catalyses:
Glutamate –> α-ketoglutarate + NH4+
Renal source of NH4+ production from glutamine
The series of deamination of glutamine:
Glutamine to glutamate (glutaminase)
Glutamate to α-ketoglutarate (glutamate dehydrogenase)
Factor affecting Renal uptake of glutamine
Depends on the need to excrete H+ to maintain blood pH.
[note: glutamine is small enough to enter glomerular filtrate]
Carbonic anhydrase
Renal enzyme, catalyze conversion of H2O and CO2 to H+ and HCO3-
H+ excreted via urine
HCO3- secreted back to blood
(control of blood pH)
Renal glutamine metabolism overview
Major fuel sources for the kidney
Lactate (normal state)
Glutamine (acidosis)
Fatty acids (fasting state)
Glucose
Renal fuel source in fed state
Lactate (45%; transported to blood-rich cortical cells for gluconeogenesis)
Glucose (25%)
Glutamate (15%)
Fatty Acid (15%)
Renal fuel source in fasting
Fatty acid (60%)
Glutamate (25%)
Lactate (15%)
Glucose (0%)
Renal fuel source in acidosis
Glutamate (40%)
Fatty acid, glucose, lactate (@ 20%)
Glutamine as renal fuel molecules
Glutamine is used as fuel in the normal fed state, and
to a greater extent during fasting and metabolic acidosis.
Source of glucose utilised in renal medulla
Glucose utilised in the renal medulla is produced in the renal cortex
Nephric blood supply overview
Blood supply to cortical (short-looped) nephrons is greater than that to the juxtamedullary/medullary (long-looped) nephrons
Glutamine metabolism in the kidney
Mitochondria:
glutamine -> glutamate -> α-ketogutarate -> [enters TCA cycle] -> Oxaloacetic acid (OAA) ->
Cytoplasm:
-> OAA -> PEP -> converted to glucose via gluconeogenesis, or pyruvate
Translocation of electrons (in form of OAA) from mitochondria to cytoplasm
Malate-aspartate shuttle:
- OAA converted to aspartate, aspartate move out of mitochondria, aspartate reconvert to OAA
- OAA converted to malate (with NADH to NAD+), malate move out of mitochondria, malate convert to OAA (NAD+ to NADH)
amino acid metabolism errors and urine
Materials excreted in urine can reflect on accumulated amino acid metabolites; therefore Inborn errors of amino acid metabolism will be manifestations in the urine
Phenylalaine metabolism errors overview
Pheylalaine Degradation
1) Main pathway:
Phenylalaine [phenylalaine hydroxylase> Tyrosine [tyrosine aminotransferase> Homogentisate [homogenisate oxidase> Fumarylacetoacetate [fumarylacetoactate hydrolase> fumarate and acetoacetate
2) Alternate pathway
Phenylalaine [transamination> Phenylpyruvate -> Phenylacetate (musty odour) and Phenyllactate
Tyrosine metabolism errors overview
Tyrosine degradation
Tyrosine [tyrosine aminotransferase> Homogentisate [homogenisate oxidase> Fumarylacetoacetate [fumarylacetoactate hydrolase> fumarate and acetoacetate
Phenylketonuria (classical)
Autosomal recessive
defective enzyme: phenylalaine hydroxylase (hepatic)
Phenylalaine cannot be converted to tyrosine; accumulation of phenylalaine which is converted to phenylpyruvate, which can be found in urine. Leads to brain and nerve damage, mental retardation
Phenylketonuria (non-classical)
defective enzyme: Dihidropteridine
Phenylalaine cannot be converted to tyrosine; accumulation of phenylalaine which is converted to phenylpyruvate, which can be found in urine. Leads to brain and nerve damage, mental retardation
Dihydropteridine
Convert quinoloid dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4). BH4 participate in the conversion of phenylalaine to tyrosine via phenylalaine hydroxylase, where it is converted to BH2. Therefore with defective dihydropteridine, BH4 cannot be regenerated from BH2, and phenylalaine-tyrosine conversion stops
Alcaptonuria
Autosomal recessive disorder to phenylalaine and tyrosine metabolic pathway
Defective enzyme: Homogentisate oxidase
Homogentisate/homogentisic acid will accumulate, leading to black urine and arthritis
Tyrosinemia I
Disorder to phenylalaine and tyrosine metabolic pathway
Missing enzyme: Fumarylacetoacetate hydrolase
Accumulation: Fumarylacetoacetate
Symptoms: Liver failure, early death
Tyrosinemia II
Disorder to phenylalaine and tyrosine metabolic pathway
Missing enzyme: tyrosine aminotransferase
Accumulation: Tyrosine
Symptoms: Neurological damage, mental retardation
Methionine metabolic error overview
Cystathioninuria
Disorder to methionine metabolic pathway
missing enzyme: cystathionase (convert cystathionine to cysteine)
Accumulation: Cystathionine
Benign cardiovascular complications and neurological problems
Homocysteinemia
Disorder to methionine metabolic pathway
missing enzyme: Methionine synthase or FH4 reductase or cysthathionine synthase
Accumulation: Cystathionine
Benign cardiovascular complications and neurological problems
Alternative fate when homocysteine builds up
Disulphide linkage of homocysteine, forming homocystine which will be excreted in urine
Branched chain amino acids
aka BCAA; leucine, isoleucine, valine
BCAA metabolism
BCAA (Leucine, isoleucine, valine) converted by branched chain α-keto acid dehydrogenase (BCKD) protein complex
Maple syrup Urine Disease (MSUD)
Disorder of BCAA metabolism
Defective BCKD (branched chain α-keto acid dehydrogenase) protein complex
accumulation of α-keto acid of BCAA
Mental retardation
Sepsis/trauma and glutamine
In sepsis and trauma, glutamine is released from skeletal muscle
Uptake by tissues - immune response tissue repair
overnight fast and glutamine
BCAA in skeletal muscles converted to glutamine and released in case of overnight fast
Amino acid release from skeletal muscle
Glutamine and alanine (derived from BCAA)
glutamine formation from amino groups of BCAA
BCAA converted to α ketoacid, which is converted to glutamate via transamination. Via enzyme glutamine synthase, glutamate is converted into glutamine with NH3 derived from glutamate through purine nucleotide cycle.
BCAA to glutamine and alanine
