Amino acid degradation pathways

Amino acid degradation pathways US Medical PG Question 1: Antigen presentation of extracellular pathogens by antigen presenting cells requires endocytosis of the antigen, followed by the degradation in the acidic environment of the formed phagolysosome. Should the phagolysosome become unable to lower its pH, what is the most likely consequence?

• A. Deficient presentation of pathogens to CD4 T-cells (Correct Answer)
• B. Deficient cell extravasation
• C. Deficient presentation of pathogens to CD8 T-cells
• D. Deficient NK cell activation
• E. Deficient expression of B7

Amino acid degradation pathways Explanation: ***Deficient presentation of pathogens to CD4 T-cells*** - The acidic environment of the **phagolysosome** is crucial for optimal **antigen degradation** and processing into peptides that can bind to **MHC class II molecules**. - Without proper acidification, peptide loading onto **MHC class II** is impaired, leading to deficient presentation of extracellular pathogens to **CD4 T-cells**. *Deficient cell extravasation* - **Cell extravasation** involves events like rolling, adhesion, and transendothelial migration, which are primarily regulated by **adhesion molecules** and **chemokines**, not phagolysosomal pH. - A defect in phagolysosomal pH would not directly impede the ability of cells to exit the vasculature. *Deficient presentation of pathogens to CD8 T-cells* - **CD8 T-cell** activation primarily involves the presentation of **intracellular antigens** via **MHC class I molecules**, which typically occurs through degradation in the **cytosol** via proteasomes. - While some cross-presentation pathways exist, the primary mechanism of CD8 T-cell antigen presentation is not dependent on the acidification of phagolysosomes for extracellular pathogens. *Deficient NK cell activation* - **Natural Killer (NK) cells** recognize and kill target cells based on the presence or absence of **MHC class I molecules** and activating ligands, not on the processing of extracellular antigens within phagolysosomes. - Their activation depends on cytokine environments and surface receptor interactions, not directly on phagolysosomal pH. *Deficient expression of B7* - **B7 molecules (CD80/CD86)** are **co-stimulatory molecules** expressed by antigen-presenting cells that are crucial for full T-cell activation. While antigen processing can influence APC activation, a specific defect in phagolysosomal pH would primarily affect the *presentation* of peptides, not the *expression* of co-stimulatory molecules. - The expression of B7 is more broadly regulated by inflammatory signals and toll-like receptor (TLR) engagement, rather than being solely dependent on proper phagolysosomal acidification.

Amino acid degradation pathways US Medical PG Question 2: A codon is an mRNA sequence consisting of 3 nucleotides that codes for an amino acid. Each position can be made up of any 4 nucleotides (A, U, G, C); therefore, there are a total of 64 (4 x 4 x 4) different codons that can be created but they only code for 20 amino acids. This is explained by the wobble phenomenon. One codon for leucine is CUU, which of the following can be another codon coding for leucine?

• A. CUA (Correct Answer)
• B. CCC
• C. UAA
• D. CCA
• E. AUG

Amino acid degradation pathways Explanation: ***CUA*** - The **wobble hypothesis** allows for non-standard base pairing at the **third position** of the codon. - Since CUU codes for leucine, a change in the third base to **A (CUA)** can often still code for the same amino acid due to degeneracy of the genetic code. *CCC* - This codon codes for **proline**, not leucine. - A change in the **second letter** of the codon almost always results in a different amino acid. *UAA* - This is one of the **stop codons** (UAA, UAG, UGA), which signals the termination of translation. - It does not code for any amino acid. *CCA* - This codon codes for **proline**, not leucine. - Changing the first or second nucleotide typically results in a different amino acid. *AUG* - This codon codes for **methionine** and also serves as the **start codon** for protein synthesis. - It does not code for leucine.

Amino acid degradation pathways US Medical PG Question 3: A group of researchers wish to develop a clinical trial assessing the efficacy of a specific medication on the urinary excretion of amphetamines in intoxicated patients. They recruit 50 patients for the treatment arm and 50 patients for the control arm of the study. Demographics are fairly balanced between the two groups. The primary end points include (1) time to recovery of mental status, (2) baseline heart rate, (3) urinary pH, and (4) specific gravity. Which medication should they use in order to achieve a statistically significant result positively favoring the intervention?

• A. Potassium citrate
• B. Ascorbic acid (Correct Answer)
• C. Tap water
• D. Sodium bicarbonate
• E. Aluminum hydroxide

Amino acid degradation pathways Explanation: ***Ascorbic acid*** - Urinary excretion of **weak bases** like amphetamines is enhanced in an **acidic urine environment**. Ascorbic acid, or vitamin C, is an acidic substance that, when administered, can significantly **lower urinary pH**. - By acidifying the urine, ascorbic acid promotes the **ionization of amphetamines** in the renal tubules, making them less lipid-soluble and decreasing their reabsorption, thereby **increasing their urinary excretion**. *Potassium citrate* - Potassium citrate is a **urinary alkalinizer**, meaning it would increase the pH of the urine. - Increasing urinary pH would **decrease the excretion of acidic drugs** and **increase the reabsorption of basic drugs** like amphetamines, which is the opposite of the desired effect. *Tap water* - Administering tap water would primarily lead to **diuresis** (increased urine production) but would have a **negligible effect on urinary pH**. - While increased urine volume can dilute the concentration of amphetamines, it does not significantly alter the **renal clearance rate based on pH**, which is crucial for weak bases. *Sodium bicarbonate* - Sodium bicarbonate is a potent **urinary alkalinizer**, used to increase the pH of the urine. - Just like potassium citrate, a higher urinary pH would **inhibit the excretion of amphetamines** by promoting their non-ionized, lipid-soluble form and increasing their reabsorption. *Aluminum hydroxide* - Aluminum hydroxide is primarily an **antacid** and phosphate binder, used for conditions like GERD or hyperphosphatemia; it has **no significant direct effect on urinary pH or amphetamine excretion**. - Its action is largely confined to the gastrointestinal tract, and it does not get absorbed in a way that would acidify the urine.

Amino acid degradation pathways US Medical PG Question 4: A 50-year-old man presents to the office with the complaint of pain in his left great toe. The pain started 2 days ago and has been progressively getting worse to the point that it is difficult to walk even a few steps. He adds that his left big toe is swollen and hot to the touch. He has never had similar symptoms in the past. He normally drinks 2–3 cans of beer every night but recently binge drank 3 nights ago. Physical examination is notable for an overweight gentleman (BMI of 35) in moderate pain, with an erythematous, swollen, and exquisitely tender left great toe. Laboratory results reveal a uric acid level of 9 mg/dL. A complete blood count shows: Hemoglobin % 12 gm/dL Hematocrit 45% Mean corpuscular volume (MCV) 90 fL Platelets 160,000/mm3 Leukocytes 8,000/mm3 Segmented neutrophils 65% Lymphocytes 25% Eosinophils 3% Monocytes 7% RBCs 5.6 million/mm3 Synovial fluid analysis shows: Cell count 55,000 cells/mm3 (80% neutrophils) Crystals negatively birefringent crystals present Culture pending Gram stain no organisms seen Which of the following is the mechanism of action of the drug that will most likely be used in the long-term management of this patient?

• A. Activates adenosine monophosphate (AMP) deaminase
• B. Inhibits renal clearance of uric acid
• C. Activates inosine monophosphate (IMP) dehydrogenase
• D. Inhibits xanthine oxidase (Correct Answer)
• E. Increases renal clearance of uric acid

Amino acid degradation pathways Explanation: ***Inhibits xanthine oxidase*** - The patient's symptoms (acute, severe pain in the **great toe**, swelling, erythema, elevated **uric acid** 9 mg/dL, and presence of **negatively birefringent crystals** in synovial fluid) are classic for an acute **gout attack**. - **Allopurinol** and **febuxostat** are long-term management drugs that work by inhibiting **xanthine oxidase**, an enzyme crucial for uric acid production, thereby reducing serum uric acid levels and preventing future attacks. *Activates adenosine monophosphate (AMP) deaminase* - This is not a mechanism of action for common long-term gout medications. AMP deaminase is involved in purine metabolism but is not a direct target for uric acid lowering. - Manipulating AMP deaminase activity is not a recognized therapeutic approach for chronic gout management. *Inhibits renal clearance of uric acid* - This mechanism would *increase* serum uric acid levels, which is contraindicated in the long-term management of gout. - Drugs that inhibit renal clearance of uric acid would exacerbate the condition, leading to more frequent and severe gout attacks. *Activates inosine monophosphate (IMP) dehydrogenase* - This is not a mechanism of action for long-term gout medications. IMP dehydrogenase is involved in de novo purine synthesis. - Inhibitors of IMP dehydrogenase, like **mycophenolate mofetil**, are used in transplant medicine and autoimmune conditions, not for lowering uric acid. *Increases renal clearance of uric acid* - Drugs like **probenecid** act as **uricosurics** by increasing the renal excretion of uric acid. While this helps lower uric acid, it is specifically contraindicated in patients with **renal stones** or impaired renal function due to the risk of stone formation. - **Uricosurics** are generally second-line agents for long-term management in patients who **under-excrete uric acid** and have good renal function.

Amino acid degradation pathways US Medical PG Question 5: A 10-day-old infant with MSUD is admitted with lethargy, poor feeding, and plasma leucine of 2000 μmol/L (normal <200). Despite BCAA-free formula, the infant's condition worsens with encephalopathy. The neonatology team proposes hemodialysis, while the genetics team suggests continuing medical management with high-calorie IV fluids. The family is concerned about invasive procedures. Evaluate the optimal management strategy.

• A. High-dose thiamine trial before considering dialysis
• B. Continue medical management and reassess in 24 hours
• C. Exchange transfusion with albumin solutions
• D. Immediate hemodialysis to rapidly lower leucine levels (Correct Answer)
• E. Start peritoneal dialysis as less invasive alternative

Amino acid degradation pathways Explanation: ***Immediate hemodialysis to rapidly lower leucine levels*** - **Extracorporeal detoxification** via hemodialysis is the most effective method to rapidly lower neurotoxic **leucine** levels when they exceed 1000 μmol/L and cause **encephalopathy**. - Rapid clearance is critical to prevent **cerebral edema** and permanent **neurological sequelae** in neonates with acute MSUD crisis. *Continue medical management and reassess in 24 hours* - Delaying definitive treatment for 24 hours in a symptomatic infant with leucine at 2000 μmol/L is dangerous and increases the risk of **brain herniation**. - Standard medical management including **BCAA-free formula** cannot clear existing toxic metabolites fast enough to reverse acute **metabolic encephalopathy**. *Start peritoneal dialysis as less invasive alternative* - **Peritoneal dialysis** is significantly slower and less efficient than hemodialysis at removing branched-chain amino acids like **leucine**. - It is not recommended as first-line therapy in a critical **metabolic emergency** when hemodialysis or continuous venovenous hemodiafiltration (CVVH) is available. *Exchange transfusion with albumin solutions* - **Exchange transfusion** is largely ineffective for MSUD because it only removes toxins from the intravascular space and does not reach the larger **intracellular pool**. - This method has been superseded by modern renal replacement therapies which offer superior **clearance rates** for small molecules. *High-dose thiamine trial before considering dialysis* - Only a small subset of MSUD patients are **thiamine-responsive**, and a trial should never delay **life-saving dialysis** in an unstable patient. - **Thiamine** acts as a cofactor for the deficient enzyme complex but will not provide the immediate **detoxification** required for a level of 2000 μmol/L.

Amino acid degradation pathways US Medical PG Question 6: A research study compares three siblings with homocystinuria: one responds to pyridoxine therapy, one responds to betaine, and one requires both treatments plus dietary restriction. All have elevated homocysteine but different methionine levels. Analyze which underlying molecular mechanism best explains the variable treatment responses among these siblings.

• A. Variable dietary methionine intake affecting phenotype expression
• B. Different epigenetic modifications of the CBS gene
• C. Varying levels of cystathionine β-synthase inhibitors
• D. Mutations in three different genes affecting homocysteine metabolism
• E. Different mutations in the same CBS gene causing varying residual enzyme activity (Correct Answer)

Amino acid degradation pathways Explanation: ***Different mutations in the same CBS gene causing varying residual enzyme activity*** - **Homocystinuria** is most commonly caused by a deficiency in **Cystathionine β-synthase (CBS)**, and **allelic heterogeneity** (different mutations in the same gene) explains why siblings may have different phenotypes and treatment responses. - Responses to **pyridoxine (B6)** occur when a mutation allows for residual enzyme activity or reduced cofactor affinity, whereas more severe mutations require **betaine** to drive the alternative **remethylation pathway**. *Mutations in three different genes affecting homocysteine metabolism* - While mutations in **MTHFR** or **methionine synthase** can cause homocystinuria, siblings typically inherit the same primary genetic defect from their parents in a **Mendelian** fashion. - Differences in **methionine levels** (some high, some low) across three different genes would be extremely unlikely within a single nuclear family compared to **allelic variation** of the CBS gene. *Variable dietary methionine intake affecting phenotype expression* - Although **methionine restriction** is a treatment, the specific physiological ability to respond to **pyridoxine** is a fixed biochemical trait determined by the **enzyme's molecular structure**. - Dietary intake alone cannot explain why one sibling’s enzyme function is restored by a **cofactor** while another's is not. *Different epigenetic modifications of the CBS gene* - **Epigenetic modifications** like methylation or histone acetylation usually affect the degree of gene expression rather than the specific **biochemical responsiveness** to a vitamin cofactor. - Classic homocystinuria is an **autosomal recessive** disorder where clinical variability is well-documented to arise from **missense mutations** rather than imprinting or epigenetic silencing. *Varying levels of cystathionine β-synthase inhibitors* - There are no clinically recognized endogenous **competitive inhibitors** of CBS that would vary so significantly between siblings to dictate distinct treatment regimens. - The treatment responses described (B6 vs. betaine) specifically target the **enzyme-cofactor interaction** or surrogate metabolic pathways, which points toward **primary structural defects** in the enzyme.

Amino acid degradation pathways US Medical PG Question 7: A 4-year-old boy presents with dark urine that turns black upon standing. His parents report that his diapers developed dark stains since infancy. Physical examination is otherwise normal. Urine analysis shows elevated homogentisic acid. What metabolic consequence is this patient at risk for developing in adulthood?

• A. Progressive intellectual disability and seizures
• B. Cardiomyopathy with heart failure
• C. Cirrhosis with portal hypertension
• D. Ochronotic arthropathy affecting spine and large joints (Correct Answer)
• E. Chronic kidney disease from renal stone formation

Amino acid degradation pathways Explanation: ***Ochronotic arthropathy affecting spine and large joints*** - This patient has **Alkaptonuria**, an autosomal recessive deficiency of **homogentisate oxidase** that causes **homogentisic acid** to accumulate and polymerize into a melanin-like pigment. - These pigments deposit in connective tissues (ochronosis), leading to debilitating **ochronotic arthropathy** in adulthood, characterized by the calcification of **intervertebral discs** and damage to large joints. *Chronic kidney disease from renal stone formation* - While some metabolic disorders like primary hyperoxaluria lead to renal failure, Alkaptonuria is primarily associated with **nephrolithiasis** (kidney stones) rather than chronic parenchymal kidney disease. - The dark urine itself is a byproduct of **homogentisic acid oxidation** and is not typically toxic to the renal tubule. *Progressive intellectual disability and seizures* - Neurological decline and seizures are characteristic of untreated **phenylketonuria (PKU)** or **maple syrup urine disease**, not Alkaptonuria. - Patients with Alkaptonuria typically have **normal intelligence** and no increased risk for seizure disorders. *Cardiomyopathy with heart failure* - Alkaptonuria is associated with **valvular heart disease** (specifically aortic or mitral stenosis) due to pigment deposition and calcification, rather than primary cardiomyopathy. - Heart failure in these patients is usually a secondary consequence of chronic **valvular calcification** rather than a direct metabolic effect on the myocardium. *Cirrhosis with portal hypertension* - Liver failure and cirrhosis are common in **tyrosinemia type I** due to the accumulation of toxic succinylacetone. - **Alkaptonuria** involves a different step in the tyrosine degradation pathway (homogentisic acid) and does not result in **hepatotoxicity** or cirrhosis.

Amino acid degradation pathways US Medical PG Question 8: A newborn screening program detects elevated leucine levels in a 3-day-old infant who appears clinically normal. Confirmatory testing shows elevated branched-chain amino acids. The parents ask about immediate treatment versus watchful waiting given the infant's current stable condition. Synthesize the most appropriate counseling and management approach.

• A. Genetic counseling with delayed treatment pending mutation analysis
• B. Reassure parents and recheck in one week since infant is asymptomatic
• C. Start treatment only if ketoacidosis develops
• D. Immediate initiation of BCAA-restricted formula regardless of symptoms (Correct Answer)
• E. Wait for development of sweet-smelling urine before treatment

Amino acid degradation pathways Explanation: ***Immediate initiation of BCAA-restricted formula regardless of symptoms*** - Early treatment is vital in **Maple Syrup Urine Disease (MSUD)** because **leucine** acts as a potent **neurotoxin**; delaying intervention until symptoms appear can lead to permanent **neurological impairment** or coma. - Management must begin immediately with a specialized formula that excludes **branched-chain amino acids (BCAAs)** to lower plasma levels and prevent **metabolic crisis** during the neonatal period. *Reassure parents and recheck in one week since infant is asymptomatic* - MSUD is a medical emergency where the "honeymoon period" of being asymptomatic lasts only a few days before rapid **metabolic decompensation** occurs. - Rechecking in one week is inappropriate as the infant would likely develop **cerebral edema** or life-threatening **ketoacidosis** within that timeframe. *Wait for development of sweet-smelling urine before treatment* - The characteristic **maple syrup odor** in urine or cerumen is often a sign that **alpha-ketoacids** are already significantly elevated, indicating a dangerous metabolic state. - Treatment should always precede the development of clinical signs to ensure optimal **neurodevelopmental outcomes**. *Start treatment only if ketoacidosis develops* - **Ketoacidosis** and hypoglycemia are late-stage manifestations of MSUD that indicate a severe, potentially irreversible **metabolic breakdown**. - The goal of newborn screening is **primary prevention**, avoiding the physiological stress and brain damage associated with acute episodes of **acidosis**. *Genetic counseling with delayed treatment pending mutation analysis* - While **mutation analysis** and genetic counseling are important for long-term management and family planning, they take too long to guide acute neonatal care. - Treatment decisions must be based on **biochemical markers** (elevated leucine) rather than waiting for genotype confirmation to avoid **encephalopathy**.

Amino acid degradation pathways US Medical PG Question 9: A 14-year-old boy with a history of intellectual disability presents to the emergency department with acute hemiparesis and altered mental status. He has ectopia lentis and marfanoid habitus. MRI shows acute ischemic stroke. Laboratory studies reveal elevated plasma homocysteine (180 μmol/L; normal <15) and methionine (65 μmol/L; normal 10-40). Genetic testing shows compound heterozygous mutations in CBS gene. Evaluate the most appropriate long-term management strategy.

• A. Cysteine supplementation with periodic plasmapheresis
• B. Lifelong anticoagulation with warfarin alone
• C. Immediate liver transplantation for enzyme replacement
• D. High-dose pyridoxine, betaine, folate, and vitamin B12 supplementation (Correct Answer)
• E. Low-methionine diet with antiplatelet therapy only

Amino acid degradation pathways Explanation: ***High-dose pyridoxine, betaine, folate, and vitamin B12 supplementation*** - This patient has **homocystinuria** due to **CBS deficiency**, where high-dose **pyridoxine (B6)** acts as a cofactor to facilitate residual enzyme activity and lower homocysteine. - **Betaine** provides an alternative pathway for homocysteine remethylation, while **folate and B12** optimize related metabolic cycles to prevent recurrent **thromboembolic events**. *Lifelong anticoagulation with warfarin alone* - While the patient has had an **ischemic stroke**, warfarin does not address the underlying **metabolic toxicity** of homocysteine, which is the primary driver of vascular damage. - Management must prioritize reducing **homocysteine levels** to prevent future clots rather than just modifying the coagulation cascade. *Low-methionine diet with antiplatelet therapy only* - A **low-methionine diet** is a cornerstone of therapy, but using it with antiplatelets alone ignores the potential for **pyridoxine responsiveness** which can significantly lower levels. - **Pharmacological supplementation** (B6, B12, folate) is medically necessary alongside diet to achieve target homocysteine levels and prevent further **intellectual decline**. *Immediate liver transplantation for enzyme replacement* - **Liver transplantation** is not a standard or primary treatment for CBS-deficient homocystinuria, regardless of the severity of the **thrombotic episode**. - The disease is primarily managed with **medical and nutritional therapy**, unlike certain other metabolic disorders where transplant provides definitive enzyme replacement. *Cysteine supplementation with periodic plasmapheresis* - **Cysteine** becomes an essential amino acid in CBS deficiency and must be supplemented, but **plasmapheresis** is not an indicated treatment for removing homocysteine. - **Chronic management** relies on dietary restriction and biochemical cofactor optimization rather than invasive, temporary measures like plasmapheresis.

Amino acid degradation pathways US Medical PG Question 10: A 25-year-old woman with a history of childhood PKU, now on a relaxed diet, is planning pregnancy. Her current phenylalanine level is 18 mg/dL. She asks about risks to her baby. Analysis of potential outcomes shows which combination of risks is most concerning if she continues current dietary habits through pregnancy?

• A. Maternal thrombosis and fetal growth restriction only
• B. Maternal seizures and gestational diabetes
• C. Fetal PKU with severe early-onset symptoms
• D. Fetal microcephaly, intellectual disability, and congenital heart defects (Correct Answer)
• E. Maternal liver failure and fetal hydrops

Amino acid degradation pathways Explanation: ***Fetal microcephaly, intellectual disability, and congenital heart defects*** - Elevated maternal **phenylalanine levels** (above 6 mg/dL) cross the placenta and act as a **teratogen**, leading to the classic **Maternal PKU Syndrome**. - This syndrome is characterized by a high risk of **microcephaly**, severe **intellectual disability**, and structural **congenital heart defects** (e.g., Tetralogy of Fallot). *Maternal seizures and gestational diabetes* - While poorly controlled PKU can affect maternal health, it is not a primary risk factor for the development of **gestational diabetes**. - The primary concern in this clinical scenario is the **teratogenic effect** on the fetus rather than specific maternal metabolic complications like diabetes. *Maternal liver failure and fetal hydrops* - PKU is an **enzymatic deficiency** (phenylalanine hydroxylase) and does not typically present with acute **liver failure** or cause **fetal hydrops**. - Fetal hydrops is more commonly associated with **Rh isoimmunization**, **congenital infections**, or severe fetal anemias. *Fetal PKU with severe early-onset symptoms* - The fetus will only have PKU if it inherits a mutated allele from both parents; the risks described are due to the **toxic maternal environment**, not the fetus's genotype. - Infants with PKU are usually asymptomatic at birth due to maternal clearance of phenylalanine; symptoms only develop after birth when they begin **protein feeds**. *Maternal thrombosis and fetal growth restriction only* - While **intrauterine growth restriction (IUGR)** is a component of Maternal PKU Syndrome, the risk is not limited to growth and thrombosis. - **Maternal thrombosis** is a more common concern in disorders like **homocystinuria**, not classic Phenylketonuria.

Amino acid degradation pathways Flashcard 1 of 10

Question: What stainable protein is abundant in astrocytes?

Answer: GFAP

Amino acid degradation pathways Flashcard 2 of 10

Question: What enzyme converts pyruvate to alanine?

Answer: alanine aminotransferase (ALT)

Amino acid degradation pathways Flashcard 3 of 10

Question: myeloperoxidase

Answer: respiratory burst

Extra Information: H2O2HOClPMNs

Amino acid degradation pathways Flashcard 4 of 10

Question: superoxide dismutase

Answer: respiratory burst

Extra Information: O2-H2O2

Amino acid degradation pathways Flashcard 5 of 10

Question: The Golgi makes modifications to some amino acids trafficking through it. What are the modifications made to threonine?

Answer: O-oligosaccharide

Amino acid degradation pathways Flashcard 6 of 10

Question: The Golgi makes modifications to some amino acids trafficking through it. What are the modifications made to asparagine?

Answer: N-oligosaccharide

Amino acid degradation pathways Flashcard 7 of 10

Question: The Golgi makes modifications to some amino acids trafficking through it. What are the modifications made to serine?

Answer: O-oligosaccharide

Amino acid degradation pathways Flashcard 8 of 10

Question: cystinuria

Answer:

Extra Information: cystine crystals in urine, staghorn calculi in renal pelvis hydration, urinary alkalinizationARamino acid transporter in PCT of kidney

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Question: Give the essential, gluconeogenic amino acids.

Answer: Met, Val, His

Amino acid degradation pathways Flashcard 10 of 10

Question: Give the essential, gluconeogenic/ketogenic amino acids.

Answer: Ile, Phe, Thr, Trp