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Biochemistry Unit 10: Lipid and Nitrogen Metabolism; Integration

Fats and amino acids are major fuels, and the body must coordinate their use with carbohydrates. This unit covers fatty acid breakdown and synthesis, ketone bodies, amino acid nitrogen disposal and how hormones integrate metabolism across tissues.

Covers: Fatty acid activation and the carnitine shuttle, β-oxidation and ATP yield, Ketone bodies, Fatty acid synthesis and its regulation, Amino acid catabolism and transamination, The urea cycle, Fed and fasting states and hormonal integration

Study guide

Stored triacylglycerols are broken down by lipases in adipose tissue, releasing fatty acids and glycerol (which the liver uses for gluconeogenesis). In the cytosol, each fatty acid is activated to acyl-CoA, costing 2 ATP equivalents (ATP → AMP + PPi). Long-chain acyl groups enter mitochondria on carnitine: CPT-I transfers them to carnitine, a translocase carries them in, and CPT-II rebuilds acyl-CoA in the matrix. CPT-I is the main control point and is inhibited by malonyl-CoA, so cells do not burn fatty acids while making them.

β-oxidation repeats four steps: oxidation by acyl-CoA dehydrogenase (FADH₂), hydration, oxidation by 3-hydroxyacyl-CoA dehydrogenase (NADH), and thiolysis releasing acetyl-CoA. A chain of 2n carbons needs n − 1 rounds and makes n acetyl-CoA. Palmitate (16:0) gives 8 acetyl-CoA, 7 NADH and 7 FADH₂, for 108 ATP, or 106 after activation. Unsaturated fats need an isomerase and give slightly less; odd-chain fats leave propionyl-CoA, which becomes succinyl-CoA and can make glucose. During fasting, the liver turns excess acetyl-CoA into ketone bodies (acetoacetate and β-hydroxybutyrate), which heart, muscle and brain can use but liver cannot.

Fatty acid synthesis happens in the cytosol of liver and adipose tissue in the fed state. Acetyl-CoA leaves mitochondria as citrate. Acetyl-CoA carboxylase (biotin, ATP) makes malonyl-CoA in the committed step; it is activated by citrate and insulin and inhibited by palmitoyl-CoA and by phosphorylation via AMP-activated kinase and glucagon. Fatty acid synthase adds two carbons per cycle from malonyl-CoA, using 2 NADPH each time, mainly supplied by the pentose phosphate pathway. Making palmitate uses 8 acetyl-CoA, 7 ATP and 14 NADPH.

Amino acids are not stored, so excess ones are broken down. Aminotransferases, using pyridoxal phosphate, move amino groups to α-ketoglutarate to make glutamate; glutamate dehydrogenase then releases NH₄⁺. Muscle sends nitrogen to the liver as alanine (glucose-alanine cycle) and glutamine. In the liver urea cycle, carbamoyl phosphate synthetase I makes carbamoyl phosphate from NH₄⁺ and HCO₃⁻; ornithine transcarbamoylase forms citrulline; aspartate adds the second nitrogen; and arginase releases urea and regenerates ornithine. Each urea costs 3 ATP (4 high-energy bonds). Carbon skeletons are glucogenic, ketogenic (only Leu and Lys purely so) or both.

Metabolism is integrated by hormones. In the fed state, insulin promotes glucose uptake (GLUT4 in muscle and fat), glycogen synthesis, glycolysis and fatty acid synthesis, mainly by dephosphorylating key enzymes. In fasting, glucagon (and epinephrine in stress) raises cAMP and PKA activity, driving glycogen breakdown, gluconeogenesis, lipolysis and ketogenesis. Tissues specialize: liver keeps blood glucose stable, muscle uses glucose, fatty acids and ketones, the brain needs glucose but adapts to ketones in prolonged fasting, and red cells use only glucose. Untreated type 1 diabetes mimics extreme fasting, causing high glucose and ketoacidosis.

Key ideas

• Fatty acids are activated in the cytosol and enter mitochondria on carnitine via CPT-I.
• Each round of β-oxidation yields 1 FADH₂, 1 NADH and 1 acetyl-CoA.
• Palmitate nets 106 ATP; fats give more ATP per carbon than glucose.
• The liver makes ketone bodies during fasting but cannot use them.
• Acetyl-CoA carboxylase and malonyl-CoA coordinate fat synthesis and oxidation.
• Amino nitrogen is collected as glutamate and disposed of as urea in the liver.
• Insulin drives storage; glucagon and epinephrine drive mobilization.

Formulas and rules

Common mistakes

• Counting n rounds of β-oxidation instead of n − 1 for a 2n-carbon fatty acid.
• Forgetting the 2-ATP activation cost when computing fatty acid ATP yield.
• Saying the liver uses ketone bodies for its own energy.
• Thinking even-chain fatty acids can make net glucose.
• Confusing NADPH (biosynthesis) with NADH (ATP production).

Before the test, make sure you can

• Describe fatty acid activation, the carnitine shuttle and the four steps of β-oxidation.
• Calculate ATP yields for saturated, unsaturated and odd-chain fatty acids.
• Explain ketone body synthesis and use and why the liver cannot use them.
• Describe fatty acid synthesis, its cost and its regulation by ACC and malonyl-CoA.
• Explain transamination, deamination and the urea cycle, including nitrogen sources.
• Classify amino acids as glucogenic or ketogenic and interpret inborn errors such as PKU and OTC deficiency.
• Compare fed and fasting metabolism and the roles of insulin and glucagon.
• Explain metabolic changes in prolonged fasting and type 1 diabetes.

Words to know

Acyl-CoA synthetase

Activates fatty acids to acyl-CoA using ATP → AMP + PPi.

Carnitine shuttle

System (CPT-I, translocase, CPT-II) that moves long-chain acyl groups into mitochondria.

CPT-I

Carnitine acyltransferase I, the rate-limiting step of fat oxidation; inhibited by malonyl-CoA.

β-oxidation

Repeated cycle that removes two-carbon acetyl-CoA units from fatty acyl-CoA.

Propionyl-CoA

Three-carbon product of odd-chain fatty acid oxidation; converted to succinyl-CoA.

Ketone bodies

Acetoacetate, β-hydroxybutyrate and acetone, made in liver from acetyl-CoA.

Thiophorase

Succinyl-CoA:acetoacetate CoA transferase, needed to use ketone bodies; absent in liver.

Acetyl-CoA carboxylase

Biotin enzyme making malonyl-CoA; committed step of fatty acid synthesis.

Fatty acid synthase

Multienzyme that builds palmitate using malonyl-CoA and NADPH.

Pentose phosphate pathway

Glucose 6-phosphate oxidation that supplies NADPH and ribose 5-phosphate.

Aminotransferase

PLP enzyme that transfers amino groups between amino acids and keto acids.

Glutamate dehydrogenase

Releases NH₄⁺ from glutamate by oxidative deamination.

Urea cycle

Liver pathway converting NH₄⁺ and aspartate nitrogen to urea.

Carbamoyl phosphate synthetase I

Mitochondrial urea cycle enzyme; activated by N-acetylglutamate.

Ketogenic amino acid

One broken down to acetyl-CoA or acetoacetate; Leu and Lys are purely ketogenic.

Glucose-alanine cycle

Muscle sends alanine to liver, which uses its carbon for glucose and nitrogen for urea.

Insulin

Fed-state hormone promoting glucose uptake and storage of glycogen and fat.

Glucagon

Fasting hormone promoting glycogen breakdown, gluconeogenesis and ketogenesis.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.