inborn errors of metabolism Flashcards
Inborn Errors of Metabolism
what are they
what causes them
“Inborn errors” of metabolism (e.g., CHO, lipid, protein) result from variation in the structure or function of enzymes or
protein molecules (e.g., structural or transport proteins)
The cause of an inborn error of metabolism is a genetic mutation or the absence of the gene (which codes for this
particular enzyme or protein)
When this happens to an enzyme (most autosomal recessive), the enzyme activity is decreased or missing (i.e.,
heterogeneous disorders)
The result is a block in a metabolic pathway (inborn error discussed in class e.g., cystic fibrosis)
Disorders of Branched Chain Amino Acid Metabolism
Structure
isoleucine:
leucine:
valine
Metabolism
Occurs in muscle tissue: BCAA transferase/transaminase
- Structural similarity between BCAAs
- Catabolism initially involves the same reactions
A. Transmination
B. Oxidative Decarboxylation to Acyl-CoA Thioesters
C. Dehydrogenation to α,β-Unsaturated Acyl-CoA Thioesters
- Common pathway diverges, and each amino acid follows its own unique pathway to amphibolic intermediates
- Nature of end-products
- Disorders of BCAA Metabolism
MAPLE SYRUP URINE DISEASE
Propionic Acidemia
A. Transmination
B. Oxidative Decarboxylation to Acyl-CoA Thioesters
C. Dehydrogenation to α,β-Unsaturated Acyl-CoA Thioesters
Transamination
- Reversible transamination of all 3 branched L-α-amino acids in mammalian tissues is due to catalysis by a
pyridoxal phosphate requiring transaminase
- The reversibility of this reaction accounts for the ability of the corresponding α-keto acids to replace a dietary
requirement for the L-α-amino acids.
B. Oxidative Decarboxylation to Acyl-CoA Thioesters
- These irreversible reactions closely resemble the analogous oxidations of pyruvate to CO2 and acetyl-CoA and
of α-ketoglurate to CO2 and succinyl-CoA
- Oxidative decarboxylation uses of a four-protein, three enzyme complex (branched-chain keto acid
dehydrogenase complex).
- Complex is located on the inner mitochondrial membrane and requires the coenzymes thiamin pyrophosphate,
lipoic acid, CoA, and NAD+
- In maple syrup urine disease, a rare genetic defect in infants, a metabolic block due to a nonfunctional
oxidative decarboxylase prevents further catabolism of all 3 α-keto acids
- These acids (and corresponding amino acids) accumulate in the blood and urine, imparting to urine the
charactistic odor for which the defect is named.
C. Dehydrogenation to α,β-Unsaturated Acyl-CoA Thioesters
- Reaction is analogous to dehydrogenation of straight chain acyl-CoA thioesters in fatty acid catabolism
- Isovaleric acidemia (MSUD variant if isovaleryl-CoA dehydrogenase enzyme is absent) follows the ingestion of
protein-rich foods, there occurs an increase of isovalerate in the blood. An increase in other branched α-keto
acids does not occur. A defect of leucine catabolism.
Reaction is analogous to dehydrogenation of straight chain acyl-CoA thioesters in fatty acid catabolism
- Isovaleric acidemia (MSUD variant if isovaleryl-CoA dehydrogenase enzyme is absent) follows the ingestion of
protein-rich foods, there occurs an increase of isovalerate in the blood. An increase in other branched α-keto
acids does not occur. A defect of leucine catabolism.
- Disorders of BCAA Metabolism
Case Study: Propionic Acidemia
Case Study: Propionic Acidemia
A boy was born to a couple who had not had any children. The pregnancy and delivery were
unremarkable. At three days of age, he began vomiting and appeared ill. Routine analysis of his
urine showed the presence of a large amount of ketones. His blood pH was low. Analysis of the
organic acids in his urine showed several abnormal metabolites including methylcitrate,
butanone, pentanone, and various ketoacids which are combinations of acetate and propionate.
Propionyl-CoA (an end-product of BCAA metabolism) is normally converted to methylmalonylCoA
(which later is converted to succinyl-CoA) by the enzyme propionyl-CoA carboxylase. The
reaction uses CO2 and ATP. Biotin is a cofactor in the reaction.
One cause of the propionic acidemia (and there are many others, such as Vitamin B12 deficiency)
could be a biotinidase deficiency which is a fairly common disorder in people of northern
European descent, affecting about 1/25,000 individuals. Because they only get one use out of
biotin, they either have to take in massive amounts of biotin each day (about 200 times the
recommended daily allowance) or they become functionally biotin deficient. Their most prominent
symptoms are a scaly skin rash, hearing loss and neurologic impairment. Similar symptoms have
been reported in individuals who consume large amounts of raw egg whites. Egg white contains a
protein called avidin which binds biotin nearly as strongly as if it were covalently linked. The
symptoms are due to severe biotin deficiency.
Treatment of Propionyl-CoA and Methymalonyl-CoA Defects
Propionyl-CoA comes from several sources: breakdown of odd chain fatty acids (these are very
uncommon in our diets), and catabolism of the amino acids valine, isoleucine, threonine and
methionine. In children with defects in propionylCoA and methylmalonylCoA metabolism, the
amount of propionate produced is minimized by limiting the amount of propioinogenic substances
in the diet. The special diet is often referred to as VOMIT, since it is restricted in Valine, Odd
chain fatty acids, Methionine, Isoleucine and Threonine. Since most children with these disorders
vomit, the diet is particularly appropriate.
MAPLE SYRUP URINE DISEASE
- Group of inherited disorders of isoleucine, leucine, and valine metabolism resulting from several different
mutations that impair branched-chain ketoacid dehydrogenase
(varying degrees and symptoms are the result) - Infants appear normal at birth and are clinically well until after eating a protein-containing feed.
- The most severely impaired enzymes may produce seizures, apnea, and death within 10 days of birth.
- Neurological impairment is manifested by poor sucking, irregular respiration, rigidity alternating with flaccidity and
seizures. - Untreated patients who survive beyond early infancy have retarded physical and mental development.
- Early diagnosis and therapy lead to normal growth and development.
SCREENING - Apnea and death may be the first clinical manifestations of the disorder; thus, screening is
important in identified groups (PKU is automatic) - Incidence appears to be 1 in 216,000 (1 per 116,000 in Blacks)
DIAGNOSIS - Blood and urinary levels of BCAAs and BC-ketoacids measured by chromatography (HPLC) - Classic MSUD have blood leucine level greater than 610 μmol/L at 72 h of age
TREATMENT - Diet consisting of BCAA-free protein and energy (problem?) - Long-term therapy is a diet that maintains plasma concentrations of BCAAs and allow maximal
development of intellect while supplying adequate energy, protein, and other nutrients for
optimal growth - Diet formulations based on nutrient requirements
screening for maple syrup urine disease
Apnea and death may be the first clinical manifestations of the disorder; thus, screening is
important in identified groups (PKU is automatic)
- Incidence appears to be 1 in 216,000 (1 per 116,000 in Blacks)
DIAGNOSIS for maple syrup
Blood and urinary levels of BCAAs and BC-ketoacids measured by chromatography (HPLC)
- Classic MSUD have blood leucine level greater than 610 μmol/L at 72 h of age
TREATMENT
Diet consisting of BCAA-free protein and energy (problem?)
- Long-term therapy is a diet that maintains plasma concentrations of BCAAs and allow maximal
development of intellect while supplying adequate energy, protein, and other nutrients for
optimal growth
- Diet formulations based on nutrient requirements
Disorders of Aromatic Amino Acid Metabolism
Structure
phenylalanine:
tyrosine:
- Metabolism: Aromatic Amino Acids
A. Formation of Tyrosine
- Tyrosine is formed from phenylalanine by the reaction catalysed by phenylalaine hydroxylase.
- Thus, tyrosine is not a nutritionally essential amino acid provided the diet contains adequate quantities
of phenylalanine (conditionally indispensable amino acid)
- Phenylalanine is essential in the diet, as the reaction is not reversible
- The phenylalanine hydroxylase complex is a mixed-function oxygenase present in mammalian liver
but absent from other tissue
- Reaction involves the incorporation of one atom of molecular oxygen into the para position of
phenylalanine while the other atom is reduced, forming water.
- Reducing power in is supplied by NADPH through tetrahydrobiopterin, which resembles folic acid.
B. Transamination of tyrosine forms p-hydroxyphenylpyruvate
- Catalyzed by tyrosine-α-ketoglutarate transaminase, an inducible enzyme of mammalian liver
C. Hydroxyphenylpyruvate oxidase, Cu metalloprotein, oxidizes p-hydroxphenylpyruvate to homogentisate
- Ascorbate (Vit C) is the reductant, so scorbutic patients excrete incompletely oxidized products of
tyrosin metabolism
D. Homogentisate oxidase, an Fe metalloprotein, opens the aromatic ring.
Isomerization followed by hydrolysis forms fumarate plus acetoacetate
- Cis to trans isomerization is catalyzed by maleylacetoacetate cis, trans isomerase.
- Fumarylacetoacetate is hydrolysed by fumarylacetoacetate hydrolase forming fumarate (TCA cycle,
glucogenic) a
