Amino Acid Metabolism Chapter 3

Amino Acid Metabolism 3

• Excess nitrogen, in mammals, is converted to urea and excreted
• Carbon atoms from degraded amino acids become major metabolic intermediates
• These intermediates can be converted to glucose or oxidized via the citric acid cycle
• Examples of intermediates include pyruvate, acetyl CoA, acetoacetyl CoA, α-ketoglutarate, succinyl CoA, fumarate, and oxaloacetate
• Some amino acids are purely ketogenic
• Others are solely glucogenic
• Some amino acids are both glucogenic and ketogenic

Ketogenic and Glucogenic Amino Acids

• Ketogenic amino acids are degraded to acetyl CoA or acetoacetyl CoA
  • These can lead to ketone bodies or fatty acids
• Glucogenic amino acids are degraded to pyruvate, α-ketoglutarate, succinyl CoA, fumarate, or oxaloacetate
  • These can be used to produce glucose
• Only leucine and lysine are solely ketogenic
• Isoleucine, phenylalanine, tryptophan, and tyrosine are both ketogenic and gluconeogenic

Diseases Associated with Amino Acid Metabolism

• Inborn Errors of amino acid metabolism
  • Diseases caused by enzyme deficiencies
  • Examples:
    • Citrullinemia (Arginosuccinate lyase deficiency)
    • Tyrosinemia (various tyrosine degradation enzyme deficiencies)
    • Albinism (Tyrosinase deficiency)
    • Homocystinuria (Cystathionine β-synthase deficiency)
    • Hyperlysinemia (α-aminoadipic semialdehyde dehydrogenase deficiency)

Detailed Analysis of Specific Diseases

Cystathionuria

• Cystathionuria is relatively common in premature infants
• In adults, genetic deficiency of cystathionase can cause cystathionuria
• Benign condition

Homocystinuria

• Deficiencies in cystathionine and cystathionine synthase enzymes cause this condition
• Results in increased homocystine and methionine in the blood
• Type III and II are caused by deficiencies of 5-methyltetrahydrofolate and vitamin B12, respectively
• Eye problems, bone problems, vascular damage, thrombi, and emboli are potential complications
• Zonal fibres in the eye may fray and break leading to dislocation of the lens
• Osteoporosis and spine curvature can occur
• Long bones may elongate
• High homocysteine correlates with atherosclerosis and heart attack

Phenylketonuria (PKU)

• Autosomal recessive disorder, defect in phenylalanine hydroxylase
• Deficiency in phenylalanine hydroxylase, B6, tetrahydrobiopterin, or tetra hydrobiopterin reductase
• Increased phenylalanine levels in patients, normal levels are <1-2mg/dL
• Mental retardation, delayed psychomotor maturation, tremors, seizures, eczema, and hyperactivity
• Special semi-synthetic preparations such as Lofenalac (casein substitute) are used to restrict dietary phenylalanine

Tyrosinaemia

• Frequently observed in premature newborns. Conditions appear benign. Dietary restrictions return tyrosine to normal levels
• Tyrosinaemia II results from a deficiency of tyrosine aminotransferase- May involve eye and skin lesions as well as neurological problems.
• Tyrosinaemia I (tyrosinosis) is caused by the genetic deficiency of fumarylacetoacetate hydrolase- Acute form is associated with liver failure and a cabbage-like odour, and death within the first year of life.
• Tyrosinaemia I symptoms potentially include a cabbage-like odour

Alcaptonuria

• Occurs when homogentisate can't be further oxidized (homogentisate oxidase)
• Homogentisate accumulates and auto-oxidizes, forming dark pigment that discolors urine
• Chronic accumulation in cartilage can cause arthritic joint pain
• Urine can become black upon standing, or turn red-brown if exposed to air or alkali

Maple Syrup Urine Disease (MSUD)

• Due to a deficiency in α-keto acid dehydrogenase in branched-chain amino acids.
• Leads to mental and physical retardation.
• Urine has a distinctive maple syrup odor

Screening for MSUD

• Screening of newborn urine using 2,4-dinitrophenylhydrazine
• Reacts with α-ketoacids to form 2,4-dinitrophenylhydrazone derivatives

Amino Acids as Precursors to Other Biomolecules

• Amino acids are precursors for various biomolecules such as:
  • Adenine, Cytosine, Histamine, Serotonin, Thyroxine, Epinephrine, Creatine.
• These include important neurotransmitters and nucleotides
• Tyrosine is a precursor to thyroid hormones, catecholamines (e.g., dopamine, norepinephrine, adrenaline), and melanin
• Tryptophan is a precursor to serotonin and melatonin
• Amino acids are precursors to important molecules like haem, neurotransmitters, and nucleotide bases

Creatine Biosynthesis

• Synthesized in the liver by methylation of guanidoacetate
• Guanidoacetate is produced in the kidneys from arginine and glycine
• Creatine is used as a storage form of high-energy phosphate.
• Creatine phosphate donates phosphate to ADP when energy demand is high.
• Creatinine is formed in muscles from spontaneous creatine phosphate breakdown through a non-enzymatic dehydration and phosphate loss. Creatinine production is relatively steady, around 1.8 g per day. The SLC6A8 transporter brings creatine into cells (with 2Na+ and a Cl−). The transporter is insulin-sensitive.

Porphyrins

• The first step involves Gly combining with succinyl CoA.
• Catalyzed by the mitochondrial PLP enzyme δ-aminolevulinate synthase
• The carboxyl group of Gly is lost as CO2

Porphyrias

• Inherited or acquired disorders caused by enzyme deficiency in heme biosynthesis pathway
• Examples include congenital erythropoietic porphyria, caused by insufficient cosynthase; symptoms include red urine and skin sensitive to UV light
• Symptoms vary depending on the specific enzyme deficiency

Acute Intermittent Porphyria

• Characterized by overproduction of porphobilinogen and δ-aminolevulinate
• Due to the deficiency in porphobilinogen deaminase
• Severe abdominal pain and neurological dysfunction
• Attacks can be triggered by drugs like barbiturates which increases the synthesis of hepatic CytP450

Biosynthesis of Purines and Pyrimidines

• Amino acids are needed for purines and pyrimidines biosynthesis

Purine Degradation

• Source of NH4+ and uric acid
• Enzymes involved include adenosine deaminase, hypoxanthine guanine phosphoribosyltransferase, purine nucleotide phosphorylase, xanthine oxidase and others.
• Allopurinol inhibits xanthine oxidase

Diseases with Purine Degradation

• Severe combined immunodeficiency (SCID) is an inborn error of metabolism involving adenosine deaminase, leading to reduced T and B lymphocytes and impairments in DNA synthesis.
• Self-mutilation behaviours can be observed
• Gout involves excessive uric acid in circulation, which can crystalize out and cause inflammation.
• Treated with Allopurinol to inhibit xanthine oxidase

Explore the fascinating world of amino acid metabolism in this quiz. Learn about the conversion of excess nitrogen to urea, the role of metabolic intermediates, and the distinction between ketogenic and glucogenic amino acids. Test your knowledge and discover the implications for energy production and metabolic diseases.