Breaking down glycolytic regulation

academics biochemistry biology
By Rakeeb

You can stare at or redraw the pathway for glycolysis to memorize it, but obtaining a deeper understanding of cellular and tissue metabolism requires an understanding of the regulatory mechanisms governing glycolysis. Below you can find a figure of the steps for glycolysis as a reference as we discuss the regulation.

There are two major phases of glycolysis, which are often referred to as the preparatory phase (requires the investment of 2 ATP), and the payoff phase (yields 4 ATP), with a net gain of 2 ATP. Let’s put ourselves in the shoes of nature and ask if we were to regulate glycolysis, at what step should we do so? 

Early in the pathway 

If we regulate a pathway early, we can avoid unnecessarily investing energy in the preparatory phase. If we, for example, regulate the enzyme aldolase that catalyzes step 4 (a later step), then we would have invested two ATP molecules with no return, which would be wasteful for the cell. What if, instead, we negatively regulated hexokinase during energy sufficiency to prevent any consumption of ATP? It seems simplest to target the first step, but there are indeed more factors to consider.

Unique to the pathway

We also want to regulate a unique pathway to prevent negatively impacting other pathways. For instance, during energy sufficiency, a cell may want to store its free glucose in reserves. Cells can store their glucose in the form of glycogen, however, one of the initial substrates for glycogen synthesis is glucose 6-phosphate. I hope you can begin to see the problem with regulating hexokinase for glycolysis regulation. During energy sufficiency, we would aim to reduce the rate of glycolysis while also storing our nutrients for later use. By inhibiting hexokinase, we accomplish the goal of slowing down glycolysis, but we do so at the cost of glycogen synthesis (as well as other pathways such as the pentose phosphate pathway, which is important for nucleotide synthesis).

Irreversible Step

Pathways often include steps that release a large quantity of free energy, making those steps irreversible. Once an irreversible step is completed, the cell has, in some ways, committed to that pathway. When regulating a pathway, then, it is useful to consider where these large releases of free energy are, and if we can target these irreversible steps. When we look at these three characteristics, we begin to understand why nature “chose” phosphofructokinase-1 (PFK-1) as an important regulatory step of glycolysis. It is early enough to prevent wasting a second ATP molecule (step 3), it is unique to the pathway, and it catalyzes an irreversible step in glycolysis.

 

Molecules that regulate PFK-1 

Consequently, we next ask what molecules could regulate PFK-1? ATP, AMP, ADP, citrate, and fructose 2,6 bisphosphate regulate PFK-1 activity but are they stimulatory or inhibitory? If we think about the end goals of glycolysis, we can find the answer to this question. ATP is one of the products of glycolysis, and when there are sufficient amounts of ATP, we may not need rapid glycolysis; ATP can negatively regulate PFK-1 activity. Essentially, ATP tells PFK-1, “hey we have enough energy you can rest.” Conversely, ATP’s energy can be utilized with the release of AMP and ADP and therefore, high concentrations of ADP or AMP are indicative of less energy available. Naturally, AMP and ADP stimulate PFK-1 activity – ‘hey, we need to produce more energy!’ Citrate’s regulatory role can seem confusing at first, but if we break down the steps it becomes clearer. When oxygen is available, the final product of glycolysis, pyruvate, can travel to the mitochondria and be converted to Acetyl-CoA. Here it will react with oxaloacetate to form citrate, which then proceeds through the citric acid cycle. If there are higher levels of citrate, it indicates that more acetyl-CoA, and therefore, pyruvate, is available indicating a high rate of glycolysis. However, if citrate is not being consumed as quickly as it is produced then the rate of the citric acid cycle is slower than that of glycolysis. Accordingly, citrate negatively regulates PFK-1 to allow the citric acid cycle to catch up. Fructose 2,6-bisphosphate stimulates PFK-1 but is outside the scope of this walkthrough (regulated by insulin, glucagon, and other molecules).

 

I hope this modest explanation has helped you understand glycolysis regulation. More importantly, I hope it has helped you realize that, as you make your way through biochemistry (and further into your scientific endeavors), it is equally as important that you learn to question each pathway you learn – in your studying, mutate each enzyme, and walk through the ramifications on not only that pathway, but any other related ones. Consider interactions between pathways and their products, and how a single mutation can reverberate through many biological processes. Human diseases often arise this way – this exercise is not only useful for your coursework, but if you happen to have aspirations beyond completing your biology or biochemistry course, the mindset you cultivate can allow you to excel in medicine, research, and so many other fields.

Rakeeb graduated summa cum laude from Cornell University with a degree in Biological Engineering. He then pursued a research position at Johns Hopkins University, where he discovered a passion for immunology that has since led him to become a PhD candidate in the Immunology program at Harvard.

Comments

topicTopics
academics study skills MCAT medical school admissions SAT college admissions expository writing strategy English MD/PhD admissions writing LSAT physics GMAT GRE chemistry biology math graduate admissions academic advice interview prep law school admissions ACT language learning test anxiety premed career advice MBA admissions personal statements homework help AP exams creative writing MD test prep study schedules computer science Common Application mathematics summer activities history secondary applications philosophy organic chemistry economics research supplements grammar 1L PSAT admissions coaching dental admissions law psychology statistics & probability legal studies ESL CARS PhD admissions SSAT covid-19 logic games reading comprehension calculus engineering USMLE mentorship Spanish parents Latin biochemistry case coaching verbal reasoning AMCAS DAT English literature STEM admissions advice excel medical school political science skills French Linguistics MBA coursework Tutoring Approaches academic integrity astrophysics chinese dental school gap year genetics letters of recommendation mechanical engineering units Anki DO Social Advocacy algebra art history artificial intelligence business careers cell biology classics data science diversity statement geometry kinematics linear algebra mental health presentations quantitative reasoning study abroad tech industry technical interviews time management work and activities 2L AAMC DMD IB exams ISEE MD/PhD programs Sentence Correction adjusting to college algorithms amino acids analysis essay athletics business skills cold emails fellowships finance first generation student functions graphing information sessions international students internships logic networking poetry proofs resume revising science social sciences software engineering trigonometry writer's block 3L Academic Interest EMT FlexMed Fourier Series Greek Health Professional Shortage Area Italian JD/MBA admissions Lagrange multipliers London MD vs PhD MMI Montessori National Health Service Corps Pythagorean Theorem Python Shakespeare Step 2 TMDSAS Taylor Series Truss Analysis Zoom acids and bases active learning architecture argumentative writing art art and design schools art portfolios bacteriology bibliographies biomedicine brain teaser burnout campus visits cantonese capacitors capital markets central limit theorem centrifugal force chem/phys chemical engineering chess chromatography class participation climate change clinical experience community service constitutional law consulting cover letters curriculum dementia demonstrated interest dimensional analysis distance learning econometrics electric engineering electricity and magnetism escape velocity evolution executive function extracurriculars freewriting genomics harmonics health policy history of medicine history of science hybrid vehicles hydrophobic effect ideal gas law immunology induction infinite institutional actions integrated reasoning intermolecular forces intern investing investment banking lab reports letter of continued interest linear maps mandarin chinese matrices mba medical physics meiosis microeconomics mitosis mnemonics