Degradation of Amino Acids 2: The Fate of the Carbon Core Flashcards
Fate of carbon core of amino acids
- Fed: energy resources
- Glycogen, TAG
- Fasting: energy production
- Co2
- Pyr
- TCA intmd.
- Acetyl CoA, acetoacetate
Degdation of amino acids
- Glucogenic AA → TCA intmd or PYR →LIVERGlucose
- Ketogenic AA → Acetoacetate or Acetyl CoA →LIVER KB
Conditionally essential AA
The sulfur of cysteine comes from methionine
Tyrosine is produced from phenylalanine
Arginine is not essential for adults, but it is essential for children
Outline of non-essential AA synthesis
- Core of non-essential aa (10)
- Tyrosine (1)
The carbon cores of 10 non-essential amino acids derive from glucose.
Tyrosine is produced by the hydroxylation of phenylalanine
Coenzymes in amino acid metabolism
transamination & deamination
Pyridoxal-Phosphate (B6)
Coenzymes in amino acid metabolism
Methionine metabolism
Cobalamins (B12)
Coenzymes in amino acid metabolism
Hydrxylation of phenylalanine, tyrosine and tryptophan
Tetrahydrobiopterin
Coenzymes in amino acid metabolism
Oxidative decarboxylation of BCAA
Thiamine-Pyrophosphate (B1)
and
Lipoate
Antileukemic drug
Asparginase
Asn is required for the growth of fast dividing cells.
- Asn A→ Asp B→ OXA
- (AsparginaseA , ASTB )
- Recall: AST converts 2-ketoglutrate to Glu, and Asp to OXA)
- Asp → Purines and pyrimidines → RNA/ DNA (of fast dividing leukemic cells.
AA’s that are degraded to a-ketoglutarate (aKGlu)
Glu, Gln, Pro, Arg, His
Gln → Glu ⇔ aKGlu
Arg → Ornithine ⇔ Glu semialdehyde → Glu ⇔ aKGlu
Proline → Glu semialdehyde → Glu ⇔ aKGlu
Histidine → FIGLu → Glu ⇔ aKGlu
FIGlu levels (urine)
Pts with follic acid deficiency
Patients with folic acid deficiency excrete increased amounts of FIGlu in their urine.
FIGlu excretion is used to monitor folic acid deficiency
Histidinemia
Biomarkers Blood and urine
Hint (histidine metabolism)
Deficiency in histidase (an enzyme for histidine metabolism)
Biomarker: Elevated levels of histidine in both blood and urine
His A→ Urocanic acid →→ FIGlu THF→ Glu→ a-Ketoglutarate
A - Histidase
Note: Patients with folic acid deficiency (tetrahydrofolate) excrete increased amounts of FIGlu in their urine
Histamine synthesis
rxn
Enzyne
Histidine Histidine Decarboxylase→ Histamine + CO2
AA that are degraded to pyruvate
Thr → Gly ⇔ Ser → Cys→ pyruvate ⇔ Ala
purines, creatine, heme and gluthathione all are synthesized from this amino acid as precursor
Gly
Primary rxn that produces glycine in the brain is synthesized by this enzyme
Serine hydrozymethyl transferase
Serine + THF Serine hydroxymethyl Transferase ⇔ Glycine
AA that are degraded to fumarate
Phenylalanine → Tyrosine →→→ Malylacetoacetate→ Fumarylacetoacetate
Fumarylacetoacetate → fumarate + acetoacetate
Tyrosinemia Type I
Deficient enzyme
Biomarkers
Spc. characteristics
Liver and kidney status
Tx
Fumarylacetoacetate(FAA) X→ fumarate + acetoacetate
deficiency of. fumaryl acetoacetate hydrolase
Accumulation of FAA and succinyl acetone in urine
Cabage like odor
Liver failure
Renal tubular acidosis
Tx: diet restriction of phenyl alanine and tyrosine
Alkaptonuria
Disease of the tyrosine degradation pathway.
Due to homogentisic acid oxidase deficiency.
Homogentisic acid accumulates in urine and tissues
Homogentisic acid accumulation in cartilage causes crippling arthritis (dense black deposits).
Urine turns dark within minutes
Scalera bluish-black pigment (generally the first sign) and in the cartilage of the ear.
Oculocutaneous Albinism Type 1
- Due to tyrosinase deficiency
- White skin, white hair, pink eyes
- Eye and skin sensitive to sunlight
- Nystagmus, far or near-sightedness
Biologically important metabolites of Tyrosine
- Melanin (req. tyrosinase)
- Catecholamine (req. tyrosine hydroxylase and BH4)
PKU
Causes
Tx
Deficient phenylalanine hydroxylase
Mutations in the enzyme
Insufficient tetrahydrobiopterin (BH4)
Treatment: Phe-restricted, Tyr supplemented diet
Avoid aspartame, artificial sweetener
PKU Sx
- Elevated phenylalanine, phenylpyruvate, phenyllactate and phenylacetate in blood and urine (musty odor of urine).
- Neurological problems (mental retardation,seizures, tremors, microcephaly etc) due to reduced production of catecholamines.
- Hypopigmentation (light skin, hair, blue eyes) due to reduced melanin production.
The role of tetrahydrobiopterin in neurotransmitter synthesis
Severity of its deficiency
Necessary for hydroxylation of:
- Phenylalanine (tyrosine production)
- Tyrosine (first step of catecholamine synthesis)
- Tryptophan (first step of serotonin and melatonin synthesis)
Note: BH4 deficiency causes more severe phenylketonuria than mutations in phenylalanine hydroxylase
Amino acids that are degraded to Succinyl CoA
Methionine, threonine, valine and isoleucin
A- Brief summary of the rxn of aa degredation to succinyl CoA, and indicate how each of the following aas feed into it
- methionine
- threonine
- valine
- isoleucin
B- List the diseases that might occur along these pathways
a-KGlu→ propionyl CoA →methylmalonyl CoA→ Succinyl CoA
- methionine ⇒ a-Kglu
- threonine → a-KGlu
- Valine ⇒methylmalonyl semialdehyde →Priopionyl CoA
- isoleucine⇒ methylmalonyl semialdehyde →Priopionyl CoA
B- Organic acidimia, which leads to secondary hyperammonemia
- methylmalonic acidemia
- propionic acidemia
Diseases associated with the following pathway
aa degradation to succinyl CoA
Organic acidemia (general term) → 2ndhyperammonemia
Methylmalonic acidemia and priopionic acidemia
Causes of the following conditions:
- methylmalonic acidemia
- propionic acidemia
Propionyl CoA <strong>Carboxylase-Biotin</strong> → → methylmalonyl CoA Mutase B12→ Succinyl CoA
- Priopionyl CoA carboxylase deficiency
- Methylmalonyl CoA mutase deficiency
Priopionyl CoA carboxylase deficiency
priopionic acidemia (aa degdatation to succinyl CoA)
Organic acidemia due to elevated levels of 3-OH propionic acid
Organic acidimia leads to secondary hyperammonemia
Methylmalonyl CoA mutase deficiency
methylmalonic acidemia (aa degdradation to succiny CoA)
elevated levels of methylmalony acid in blood
Methionine metabolism
Homocystine Formation
S-Adenosylmethionine (SAM) is the primary methyl donor in the human body.
It participates in the synthesis of:
- phosphatidylcholine (cell membrane lipid)
- creatine (muscle energy metabolism)
- carnitine (fatty acid degradation)
- melatonin (sleep-wake hormone)
- epinephrine (“flight and fright” hormone)
The biosynthetic reactions that rely on S-adenosylmethionine as primary methyl donor
- phosphatidylcholine (cell membrane lipid)
- creatine (muscle energy metabolism)
- carnitine (fatty acid degradation)
- melatonin (sleep-wake hormone)
- epinephrine (“flight and fright” hormone)
Methionine metabolism : formation of homocysteine
Rxn
L-methionin → SAM→ SA-homocystine → homocystine
SAM: S-Adenosyl Methionione
SA: S-adenosyl
Homocystinuria management:
Homocystinuria management: Restrict methionine, supplement cysteine
Methionine metabolism: degradation of homocystine
Name 2 key enzymes and diseases assoicated with their dificiencies
Homocystine Cistathione Synthase→Cystathionine <strong>Cystathionase</strong>→ Cistine
-
Cistathione synthase deficiency- Cyctathioninuria
- elevated U. homocystine
- elevated bld. methionina
-
Cystathionase dificiency- homocystinuria
- elevated cystathionine
High level of bld homocysteine is a risk factor for
myocardial infarction
The cofactors required for transsulfuration rxns that lead to cystine formation (from homocystine)
Hint: methionine degradation
pyridoxine- B6
Methionine metabolism : degradation of homocysteine
What are the requirement for remethylation rxns?
- Cofactor
- Coenzyme
Cofactor: folate
Coenzymes: B12 derived coenzymes
BCAA
determine ketogenic or glucogenic
Valine, Isoleucin and leucin
- Valine- Glucogenic
- Isoleucine- Glucogenic and ketogenic
- Leucine- Ketogenic
rxn type that is catalyzed by a-ketoacid dehydrogenase
oxidative decarboxylation
Factors required for proper functioning of a-ketoacid dehydrogenase
(BCAA metabolism)
Just like Pyruvate dehydrogenase complexes (PDH) it requires 5 cofactos:
- TPP
- lipoate
- FAD
- NAD
- CoASH
a-ketoacid dehydrogenase participate in oxidative decarboxylation reactions.
The first and second reactions of BCAA metabolism
Reactants
Products
Enzymes and their cofactors
The end products made from each BCAA
BCAA Transamination⇔ a-ketoacid a-ketoacid dehydrogenase⇒ X-CoA + CO2 + NADH
a-ketoacid dehydrogenase req. TPP, Lipoate, NAD, FAD, CoASH
Valine (Glucogenic) metabolism ► succinyl CoA
Leucine (Ketogenic) metaboliosm ► acetoacetate and acetyl CoA
Isoleucine ( ketogenic and glucogenic) ►acetyl CoA and succinyl CoA
Maple syrup urine disease (MSUD)
I Love Vermont Maple Syrup
- Dx
- Sx
- Tx
Dx
Elevated BCAAs, especially leucine, in blood.
Elevated branched-chain ketoacids (BCKA) in blood and especially in urine.
Sx:
Maple syrup odor of urine (by 5-7 days after birth) and of earwax (12-24 hr after birth).
Encephalopathy (lethargy, poor feeding, apnea, opisthotonus, coma)
BCAA restricted high calorie diet. Usually BCAA-free formulas, supplemented with limited amounts BCAAs. Leucine is always the most restricted.
All BCAAs are essential amino acids.
MSUD Tx
BCAA restricted high calorie diet. Usually BCAA-free formulas, supplemented with limited amounts BCAAs. Leucine is always the most restricted.
BCAAs are essential.
Pellagra
Causes and manifestation
Lack of tryptophan and niacin (vitamin B3) in diet causes pellagra (characterized by the 4 Ds – Dermatitis, Diarrhea, Dementia and if untreated Death).
Tryptophan metabolism
Lack of tryptophan and niacin (vitamin B3) in diet causes pellagra (characterized by the 4 Ds – Dermatitis, Diarrhea, Dementia and if untreated Death).
Diseases of AA metabolism
General Concepts
vRare diseases
(incidence is generally less than 1:2,000).
Can be caused by -
- Mutated enzymes (autosomal recessive).
- Insufficient co-factors.
Many have neurological symptoms.
AAs are precursors of neurotransmitters and hormones
Early detection and treatment is a must!!!
Many require dietary adjustment in protein consumption.
ketogenic family of amino acids
WIFY LK
WIFY are both ketogenic and glucogenic
LK only ketogenic
W- Trp
I- Ile
F- Phe
Y- Tyrosine
L- Leucin
K- Lysine
Amino acids that are both ketogenic and glucogenic
WIFY
Trp-Ile, Phe, Tyr
Acetyl Coa Family of aa
(based on the point where their C skeleton enter the TCA cycle)
Determine the essential aa’s
W*I*F*YL*K*
W-Trp (essential)
I-Ile (essential)
F-Phe (essential)
Y-Tyr
L-Leu (essential)
K- Lys (essential)
a- Ketoglutrate family of aa
(based on the point where their C skeleton enter the TCA cycle)
_H<span>*</span>_Q REP
H-His (essential)
Q- Gln (Glutamine)
R- Arg
E- Glu (Glutamate)
P-Proline
Succinyl CoA Family of AA
(based on the point where their C skeleton enter the TCA cycle)
VIM
Val (essential)
Ile (essential)
Met (essential)
Fumarate Family of Amino Acids
(based on the point where their C skeleton enter the TCA cycle)
FY
F-Phe
Y-Tyr
Oxaloacetate Family of AA
(based on the point where their C skeleton enter the TCA cycle)
ND
Asn- N
Asp- D
Pyruvate Family of AA
(based on the point where their C skeleton enter the TCA cycle)
CAST GW
Cys- Ala- Ser-_Thr*-Gly-_Trp*
Thr and Trp are essential aa.
rxn fascilitated by the methyl group of Met
methylation reactions as S-adenosylmethionine
SAM
Met SAM Synthetase→ SAM Methyl Transferase→ SAH
