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Department of Biochemistry
Learning Objectives
Catabolism of the Carbon Skeletons of amino acids and related
disorders:
? Catabolism of Phenylalanine and Tyrosine with genetic disorders
? Arginine, Histidine, glutamate, glutamine and proline to -ketoglutarate
? Methionine, isoleucine, threonine and valine to Succinyl CoA
? Degradation of branched chain aa (Leucine to Acetoacetate and Acetyl-CoA, Valine to -
Aminoisobutyrate and Succinyl-CoA and Isoleucine to Acetyl-CoA and Propionyl-CoA)
? Asparagine and Aspartate to Oxaloacetate
Conversion of amino acids to Specialized products
Catabolism of Phenylalanine and Tyrosine with genetic disorders
Homogentisate Oxidase/
Neonatal Tyrosinemia or
Or p-hydroxyphenylpyruvate hydroxylase
Fig18.23: Lehninger Principles of Biochemistry by David L Nelson
Disorder related to phenylalanine catabolism
Phenylketonuria (PKU)
? Genetic defect in phenylalanine hydroxylase, first enzyme in
catabolic pathway for phenylalanine, is responsible for disease
phenylketonuria (PKU),most common cause of elevated levels of
phenylalanine (hyperphenylalaninemia)
? Excess phenylalanine is transaminated to Phenylpyruvate
? The "spillover" of Phenylpyruvate (a phenylketone) into urine
? High concentration of phenylalanine itself gives rise to brain
dysfunction.
Cont--
? Phenylalanine
hydroxylase
requires
the
cofactor
tetrahydrobiopterin, which carries electrons from NADH to O2
and becomes oxidized to dihydrobiopterin
? It is subsequently reduced by enzyme dihydrobiopterin
reductase in a reaction that requires NADH
? Diet low in phenylalanine can prevent the mental retardation of
PKU
Disorder related to Tyrosine catabolism
Alkaptonuria
? Metabolic defect in alkaptonuria is a defective homogentisate oxidase the
enzyme that catalyzes homogentisate to Maleylacetoacetate
? Large amounts of homogentisate are excreted and urine darkens on
exposure to air due to oxidation of excreted homogentisate
? This autooxidizes to the corresponding quinone, which polymerizes to form
an intensely dark color
? Late in the disease, there is arthritis and connective tissue pigmentation
(ochronosis) due to oxidation of homogentisate to benzoquinone acetate,
which polymerizes and binds to connective tissue
Type I Tyrosinemia
? Several metabolic disorders are associated with the tyrosine
catabolic pathway
? Probable metabolic defect in type I tyrosinemia (tyrosinosis) is
at fumarylacetoacetate hydrolase
? Untreated acute and chronic tyrosinosis leads to death from
liver failure, renal tubular dysfunction, rickets and
polyneuropathy
Type II Tyrosinemia
? Alternate metabolites of tyrosine are also excreted in type II
tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine
aminotransferase produces accumulation and excretion of
tyrosine and metabolites
? Leads to eye and skin lesions and mental retardation
Type III Tyrosinemia
? Neonatal Tyrosinemia or type III tyrosinemia, due to lowered
activity
of
p-hydroxyphenylpyruvate
dioxygenase/
p-
hydroxyphenylpyruvate hydroxylase
? It can cause learning problems, seizures, and loss of balance
? Therapy employs a diet low in protein, tyrosine and
phenylalanine
Catabolic pathways of five aa to -ketoglutarate
Proline dehydrogenase/
1-pyrroline-5-carboxylate dehydrogenase/
Fig18.26: Lehninger Principles of Biochemistry by David L Nelson
Disorder related to Proline catabolism
Type I hyperprolinemia
? The metabolic block in type I hyperprolinemia is at proline
dehydrogenase/proline oxidase
? Some individuals with hyperprolinemia type I exhibit seizures,
intellectual disability, or other neurological or psychiatric
problems
Type II hyperprolinemia
? The metabolic block in type II hyperprolinemia is at 1-
pyrroline-5-carboxylate dehydrogenase, which also participates
in the catabolism of arginine, ornithine, and hydroxyproline
? It leads to seizures or intellectual disability.
Catabolic pathways of four aa to Succinyl-CoA
Cystathione
Fig18.27: Lehninger Principles of Biochemistry by David L Nelson
Cont--
? Catabolism of isoleucine, methionine, and valine to propionyl-
CoA
? Propionyl-CoA, product of odd-chain fatty acid degradation, is
converted, to succinyl-CoA by a series of reactions involving the
participation of biotin and coenzyme B12
Degradation and Resynthesis of Methionine
Biosynthesis of S-adenosylmethionine
from methionine and ATP is catalyzed
by methionine adenosyltransferase
(MAT)
Fig 20.8. Lippincott's Illustrated Reviews, Biochemistry, 6th Ed
Disorder related to Methionine degradation
Hyper Homocysteinemia
? Elevations in plasma homocysteine (Hcy) as a result of rare
deficiencies in cystathionine -synthase of the transsulfuration
pathway causes homocysteine to accumulate and remethylation
leads to high levels of methionine in patients
? Elevated homocysteine and decreased folic acid levels in
pregnant women are associated with increased incidence of
neural tube defects (improper closure, as in spina bifida) in fetus
Cont--
? The lens of eye is frequently dislocated after the age of 3, and other
ocular abnormalities occur
? Mental retardation is frequently the first indication of this deficiency
? Attempts at treatment include restriction of methionine intake and
feeding of betaine (or its precursor, choline)
? In some cases significant improvement by feeding pyridoxine (vit B6)
? Supplementation with folate reduces the risk of such defects
Degradation of Branched chain amino acids
? Mitochondrial branched-chain -keto acid dehydrogenase
complex consists of five components:
E1: thiamin pyrophosphate (TPP)-dependent branched chain -
ketoacid decarboxylase
E2: dihydrolipoyl transacylase (contains lipoamide)
E3: dihydrolipoamide dehydrogenase (contains FAD)
Protein kinase
Protein phosphatase
Catabolism of Leucine to Acetoacetate and Acetyl-CoA
Methylcrotonyl CoA carboxylase
-keto acid decarboxylase complex
Methylglutaconyl-CoA hydralase
Isovaleryl CoA dehydrogenase
HMG CoA lyase
Fig 29.20 and 29.21. Harper's Illustrated Biochemistry 30th Edition
Catabolism of Valine to -Aminoisobutyrate and Succinyl-CoA
Enoyl CoA hydratase
-hydroxyisobutyryl CoA hydrolase
-keto acid decarboxylase complex
Methacrylyl CoA dehydrogenase
Fig 29.20 and 29.23. Harper's Illustrated Biochemistry 30th Edition
Catabolism of Isoleucine to Acetyl-CoA and Propionyl-CoA
Amino acid transaminase
-hydroxybutyryl CoA dehydrogenase
-keto acid decarboxylase complex
Fig 29.20 and 29.22. Harper's Illustrated Biochemistry 30th Edition
Disorder related to Branch chain aa degradation
? Biochemical defect in maple syrup urine disease (MSUD)
involves -keto acid decarboxylase complex (thiamine
pyrophosphate, FAD, NAD, lipoate and CoA)
? Plasma and urinary levels of leucine, isoleucine, valine, and
their -keto acids and -hydroxy acids (reduced -keto acids)
are elevated and accumulated in blood and spil over into the
urine
? This condition is called MSUD or branched-chain ketonuria
suggests maple syrup, or burnt sugar.
? Signs and symptoms of MSUD include fatal ketoacidosis,
neurological derangements, mental retardation, and a maple
syrup odor of urine
? Early diagnosis by enzymatic analysis is essential to avoid brain
damage and early mortality by replacing dietary protein by an
aa mixture that lacks leucine, isoleucine, and valine
Catabolism of Asparagine and Aspartate to Oxaloacetate
Fig18.29: Lehninger Principles of Biochemistry by David L Nelson
Cont--
? L-asparaginase is an effective chemotherapeutic agent in the
treatment of cancers that must obtain asparagine from the
blood, particularly acute lymphoblastic leukemia.
Conversion of amino acids to Specialized
products
Introduction
? In addition to serving as building blocks for proteins, amino
acids are precursors of many nitrogen-containing compounds
that have important physiologic functions
? These molecules include porphyrins (involved in heme
biosynthesis),
hormones,
purines,
and
pyrimidines,
neurotransmitters.
Conversion of arginine, ornithine and proline to specialized products
Fig 30.1. Harper's Illustrated Biochemistry 30th Edition
Creatine & Creatinine
? Creatinine is formed in muscle
from creatine phosphate by
irreversible,
non-enzymatic
dehydration,
and
loss
of
phosphate
? Glycine, arginine, and methionine
all
participate
in
creatine
biosynthesis
Fig 30.13. Harper's Illustrated Biochemistry 30th Edition
Cont--
? Creatine converted into creatine phosphate by creatine kinase
using ATP as a phosphate donor
? Presence of creatine kinase in the plasma is indicative of heart
damage and is used in the diagnosis of myocardial infarction
Conversion of cysteine to Taurine
? Three
enzyme
catalyzed
reactions convert cysteine to
taurine
? Taurine displace the coenzyme
A moiety of cholyl-CoA to form
the bile acid taurocholic acid
Fig 30.4. Harper's Illustrated Biochemistry 30th Edition
Biosynthesis of hippurate from glycine
? Many metabolites and pharmaceuticals are
excreted as water soluble glycine conjugates
? Ex. include glycocholic acid and hippuric acid
formed from the food additive benzoate
? Many drugs, drug metabolites, and other
compounds with carboxyl groups are
conjugated with glycine, which makes them
more water-soluble and thereby facilitates
their excretion in urine
Fig 30.5. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Histidine
? Decarboxylation of histidine to
histamine is catalyzed by the pyridoxal
5-phosphate-dependent
enzyme
histidine decarboxylase
? Histamine functions in allergic
reactions and gastric secretion
Fig 30.6. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Methionine
Methionine adenosyl transferase
? These polyamines function in
cell proliferation and growth,
are growth factors for cultured
mammalian
cells, and
stabilize
intact
cells,
subcellular organelles, and
membranes
? They bear multiple positive
charges, polyamines readily
associate with DNA and RNA
Fig 30.9. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Tryptophan
? Hydroxylation of tryptophan to 5-hydroxytryptophan by liver
tryptophan hydroxylase subsequent decarboxylation forms
serotonin a potent vasoconstrictor and stimulator of smooth
muscle contraction.
? Catabolism of serotonin is initiated by deamination to 5-
hydroxyindole-3-acetate, a reaction catalyzed by monoamine
oxidase
Cont--
? N-Acetylation of serotonin, followed by its O-methylation in the
pineal body, forms melatonin
? Kidney tissue, liver tissue, and fecal bacteria all convert
tryptophan to tryptamine, then to indole 3-acetate
? The principal normal urinary catabolites of tryptophan are 5-
hydroxyindoleacetate and indole 3-acetate.
Fig 30.11. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Tyrosine
? Neural cells convert tyrosine to epinephrine and norepinephrine
? Dopa is also an intermediate in the formation of melanin,
different enzymes hydroxylate tyrosine in melanocytes
? Dopa decarboxylase, a PLP-dependent enzyme, forms
dopamine.
Cont--
? Subsequent hydroxylation, catalyzed by dopamine -oxidase
forms norepinephrine
? In
adrenal
medulla,
phenylethanolamine-N-
methyltransferaseutilizes S-adenosylmethionine to methylate
the primary amine of norepinephrine, forming epinephrine
? Tyrosine is also a precursor of triiodothyronine and thyroxine
Derivatives of Tyrosine: Epinephrine
Fig 30.12. Harper's Illustrated Biochemistry 30th Edition
Derivatives of Tyrosine: Melanin
DM Vasudevan' s Textbook of Biochemistry for Medical Students-6th Ed
Derivatives of Tyrosine: T3 and T4
DM Vasudevan' s Textbook of Biochemistry for Medical Students-6th Ed
Disorder related to Tyrosine derivative
Albinism
? A deficiency of tyrosinase in melanocytes causes one form of albinism; it is
inherited as an autosomal recessive disorder
? Pigmentation of the skin, hair and iris is reduced and the eyes may appear
pink
? Reduced pigmentation of the iris causes photosensitivity, and decreased
skin pigmentation is associated with an increased incidence of certain skin
cancers
? The tyrosinase involved in catecholamine synthesis is a different
isoenzyme, controlled by a different gene; consequently, adrenaline
(epinephrine) metabolism is normal
Metabolism of -AminoButyrate (GABA)
Active form of Vit B6
Fig 30.14. Harper's Illustrated Biochemistry 30th Edition
Disorder related to GABA
4-hydroxybutyric aciduria
? Defects in succinic semialdehyde dehydrogenase, are
responsible for 4-hydroxybutyric aciduria a rare metabolic
disorder of -aminobutyrate catabolism
? Characterized by the presence of 4-hydroxybutyrate in urine,
plasma and cerebrospinal fluid
? No present treatment is available for the accompanying mild to
severe neurologic symptoms.
Group Discussion
? Subtopics of previous and today's class discussed in groups.
? Next integrated class on Protein metabolism by me and from
department of Pediatrics (discussed inborn error of metabolism
case studies).
Thank you
This post was last modified on 05 April 2022