How to study biochemistry: learn why each pathway runs, then draw it from memory

The short answer

Study biochemistry as a story of why, not a list of molecules. For each pathway, learn first what it’s for, where it runs, in which tissues and which part of the cell, its few irreversible steps and the enzymes that control them, and when it’s switched on: after a meal or in fasting, by insulin or by glucagon. Only then add the intermediates your course asks for, and draw the pathway from memory on a blank page, checking it against the book afterwards. Then join the pathways up: what happens to glucose, fat and protein in the fed state, in fasting and in diabetes, and which inherited disorders break which step.

Test yourself rather than reread, and spread it out. Biochemistry teachers name pathway dynamics and regulation, steady state and free energy among the concepts students must grasp before they can move on (Loertscher and colleagues, 2014), which is why understanding the regulation comes before memorising the steps. Testing helps here as elsewhere: in a biochemistry course at Ulm, in Germany, students who prepared with multiple-choice questions as well as videos did better on the assessment than students who prepared with the videos and a reader (Schneider, Kühl & Kühl, 2019).

Why biochemistry is hard

Biochemistry hands you a great many names, structures and reactions at once, and pathways are usually taught one by one, as if each lived on its own page. Learned that way they blur together, and they seem pointless. Richard Glew and Eric Brass (2005) argued that this is exactly why many doubt metabolism is worth learning: it’s taught as isolated, unrelated bits. Their example was medium-chain acyl-CoA dehydrogenase deficiency, which only makes sense when you see fatty acid oxidation and glucose production together in a fasting patient.

What makes it click is a handful of ideas rather than more facts. Jennifer Loertscher and colleagues (2014), working with more than 75 biochemistry teachers and 50 students, named five threshold concepts, ideas that change how you see the subject once you’ve grasped them: steady state, the dynamics and regulation of pathways, the physical basis of interactions between molecules, the thermodynamics of how large molecules take shape, and free energy. Each of them is a why: why a step is irreversible, why a pathway runs in one direction in one state and stops in another. Learn those, and each new pathway becomes a variation on what you already know.

The usual way of revising works against you, too. Roediger and Karpicke (2006) found that students who reread a text felt more confident than those who practised recalling it, but remembered less a week later. A pathway that looks familiar on the page is not one you can draw.

The method, a step at a time

Every pathway, from glycolysis to the urea cycle, can be learned the same way: the reasons first, then a skeleton you can draw from memory, then the detail your exam needs.

1. Get the ground right first: free energy and why some reactions are irreversible, enzyme kinetics and inhibition, and the carriers, ATP for energy, NADH and FADH₂ for electrons to the respiratory chain, NADPH for building molecules and defending against oxidation.
2. For each pathway, answer five questions in writing: what is it for; where does it run, in which tissues and which compartment; what goes in and what comes out, net; which steps are irreversible and which enzymes catalyse them; and what switches it on and off, and when.
3. Close the book and draw the skeleton from memory: where it starts and ends, the irreversible steps with their enzymes, where carbon enters and leaves, and where ATP and NADH are made or used.
4. Open the book and correct the drawing in another colour. The corrections are what you review next.
5. Only then add the intermediates and structures your course asks for, a stretch of the pathway at a time, redrawing from memory each time.
6. Ask what if: an enzyme missing, no insulin, a long fast, a drug that blocks one step. Predict what builds up, what runs short and what the body does about it, before you check.
7. Link each pathway to at least one disorder or drug, and come back to it the next day and at growing gaps, redrawing it before you reread anything.

Regulation and energy: what explains each pathway

Most of a pathway’s steps are reversible and go wherever the concentrations push them. The few irreversible ones are where the cell decides, so those are the steps to know cold, with their enzymes and what activates and inhibits them. In glycolysis they are hexokinase, or glucokinase in the liver, phosphofructokinase-1 and pyruvate kinase; phosphofructokinase-1 is the main control point, slowed by ATP and citrate when the cell has energy, sped up by AMP and fructose 2,6-bisphosphate.

Pathways that run in opposite directions are switched in opposite directions, so they don’t run at once and waste energy in a futile cycle. Gluconeogenesis gets round glycolysis’s three irreversible steps with its own enzymes: pyruvate carboxylase and PEP carboxykinase, fructose 1,6-bisphosphatase and glucose 6-phosphatase. Fructose 2,6-bisphosphate speeds up one direction and slows the other. Fat works the same way: malonyl-CoA, the first molecule of fatty acid synthesis, blocks carnitine palmitoyltransferase I, the entry of fatty acids into the mitochondria, so a cell making fat isn’t burning it at the same time.

Hormones set the overall direction. Insulin, after a meal, favours storage: glycogen, fat and protein are built. Glucagon in fasting and adrenaline in stress favour release: glycogen is broken down, glucose is made, fat is mobilised. For any enzyme, ask which hormone acts on it and whether that fits what the body needs in that state. If it doesn’t fit, you’ve probably learned it the wrong way round.

Fed and fasting: put metabolism together

Exams often ask about metabolism as a whole, and the clearest way to join it up is a table: the organs down the side, liver, muscle, adipose tissue, brain and red blood cells, and three states across the top, just after a meal, an overnight fast and a prolonged fast. Fill in what each organ does with glucose, fatty acids, amino acids and ketone bodies in each state, from memory, then check it. After a meal the liver stores glycogen and makes fat, and muscle and fat take up glucose under insulin; in fasting the liver breaks down glycogen and then makes glucose from lactate, glycerol and amino acids, fat releases fatty acids, and the liver turns some of them into ketone bodies, which the brain uses more and more as the fast goes on. Red blood cells, with no mitochondria, depend on glucose throughout.

Diabetes then reads as the table gone wrong. In type 1 diabetes, with no insulin, the body acts as if it were fasting while blood glucose is high: the liver keeps making glucose, fat keeps releasing fatty acids, and ketone bodies pile up into ketoacidosis. Work it out from the table before reading about it.

Concept maps suit this, as long as you make them from memory. In a randomised study of 150 first-year medical students by Krishna Mohan Surapaneni and Ara Tekian (2013), those taught biochemistry with concept maps and clinical cases scored higher on three written tests than those taught with lectures alone. Jeffrey Karpicke and Janell Blunt (2011), though, found that practising recall produced more learning than building a concept map with the text open, and Blunt and Karpicke (2014) found that maps drawn from memory worked as recall practice. So draw the map with the book shut, then open it and fix it.

In Breef, each pathway can be its own note, linked with [[double brackets]] to the ones it feeds and the hormones that control it: a note on gluconeogenesis links to glycolysis, to the fasting state and to glucagon, and Knowledge draws them all as one map, so you can see where a pathway is still on its own.

Clinical links: inherited disorders, diabetes and drugs

Clinical links are not decoration: they make the mechanism easier to keep. Nicole Woods, Lee Brooks and Geoffrey Norman (2005) taught 36 students four neuromuscular disorders either through the basic science behind their signs or through which signs went with which disorder. On the test straight away the groups did the same, but a week later the mechanism group’s diagnostic accuracy had stayed at 0.52 while the other group’s had dropped to 0.43.

One link per pathway is enough to start. In phenylketonuria, phenylalanine hydroxylase is missing, so phenylalanine builds up. In von Gierke disease, glucose 6-phosphatase is missing, so the liver can’t release glucose and fasting brings low blood sugar. In medium-chain acyl-CoA dehydrogenase deficiency, the one Glew and Brass used, fatty acids can’t be fully burned in a fast, so ketone bodies stay low and blood sugar drops. In G6PD deficiency, red cells make too little NADPH and break down under oxidative stress. Statins block HMG-CoA reductase, the controlling step of cholesterol synthesis.

Each link is also a ready-made exam question: start from the missing enzyme and predict what builds up, what runs short and what the patient shows, then check.

A plan for the weeks before the exam

Spread your reviews from the start. Cepeda and colleagues (2008), in a study of more than 1,350 people, found that the best gap between reviews grows with how long you need to remember: about 20 to 40% of the time until the test when that was a week, about 5 to 10% when it was a year. Redraw a pathway the next day, again a few days later, then about a week later and every week or two until the exam.

Breef can do the remembering for you. Record a lecture in a note and Breef writes it up; the note comes back for review the next day and then at gaps fitted to how fast you forget, with three questions written from it each time; and once you give the course its exam date, every note that would fade by then gets a last review in the days before.

1. Six weeks out: list the pathways and topics on the syllabus, and mark each by whether you can draw it from memory and explain its regulation, partly can, or can’t. Start with the foundations, enzymes, free energy and the carriers, since everything else rests on them.
2. Weeks six to three: one pathway or topic a day with the method above, starting each day by redrawing the ones from the days before.
3. Week two: integration. Fill in the fed and fasting table from memory, work through cases, such as a long fast, type 1 diabetes and the main inherited disorders, and do past exam questions in the format your exam uses.
4. The last week: only recall. Redraw every pathway skeleton and the fed and fasting table, explain the regulation of each out loud, and look things up only to fix what you got wrong.
5. The day before: a light pass over the pathways you were shakiest on, and a full night’s sleep.

Common mistakes

Memorising every intermediate before knowing what the pathway is for. Learn the purpose and the regulation first; the steps are easier to hang on them.

Learning pathways one by one and never joining them up. Exams ask what happens in fasting, in exercise and in diabetes, across pathways and organs.

Rereading the diagrams until they look familiar. Draw them from memory, then check.

Learning regulation as a list of arrows. For each one, ask whether it fits what the body needs in that state; if you can say why, you won’t mix it up.

Skipping the clinical links. They are what makes the mechanism stay, and they’re what the questions are built on.

Leaving metabolism as a whole until the last week. Integration takes time; start filling in the fed and fasting table as soon as you’ve met the first pathways.