Biochemistry 2: Mini Lectures Flashcards
What is the “VOMIT” pathway? What is produced by this pathway?
Mnemonic used for pathways that deal with catabolic products of:
Valine
Odd-chain fatty acid
Methionine
Isoleucine
Threonine
All of these things break down to form propionyl-COA
What is the key regulated step of fatty acid synthesis (FAS)? Why would this make sense?
Acetyl-CoA carboxylase (acetyl CoA + CO2 → malonyl CoA)
This is the first step in the fatty acid synthesis pathway. Many key regulated steps are the first step, particularly if it is irreversible/requires lots of energy. This follows the pattern, as adding an extra carbon to something is both 1) very energy intensive, and 2) irreversible (you can’t interconvert easily between the 2 carbon acetyl-CoA molecule, and the 3-carbon malonyl CoA).
What inhibits the carnitine shuttle? Why would this make sense?
Malonyl-CoA inhibits the carnitine shuttle
Recall that malonyl-CoA is the product of the key-regulated step in fatty acid SYNTHESIS.
The carnitine shuttle is the highly regulated transport mechanism for fatty acid OXIDATION (breakdown). If I am making lots of fatty acids – and thus generating lots of malonyl-CoA – I wouldn’t want to be breaking down fatty acids as well!
Malonyl-CoA – how many carbons does it contain? Why would this make sense?
3 carbons. It is formed from acetyl-CoA carboxylase, the key regulated step of fatty acid synthesis, in which acetyl-CoA (2 carbons) has a 3rd carbon added to it in the form of CO2.
Why would a vitamin B12 deficiency lead to demyelination of neurons?
Disruption of methylmalonyl CoA mutase would lead to build-up of methylmalonyl CoA, which would lead to inhibition of fatty acid synthesis (FAS). If methylmalonyl CoA were incorporated into fatty acids, it would form branched-chain fatty acids. This disruption of normal FAS would lead to progressive demyelination of neurons.
How can alcohol lead to lactic acidosis?
EtOH metabolized to acetate via alcohol dehydrogenase, then acetaldehyde dehydrogenase. Each of these reactions turns NAD+ → NADH. Recall that glycolysis requires NAD+, and thus if the NAD+/NADH ratio is too low → glycolysis ↓
Lactate dehydrogenase turns pyruvate + NADH → lactate + NAD+, which regenerates NAD+ to be used in glycolysis
You’ve just binged on alcohol without eating. Why are you hypoglycemic?
Recall EtOH metabolized → acetate via alcohol dehydrogenase, then acetaldehyde dehydrogenase. Each of these reactions turns NAD+ → NADH.
Also, recall these 2 important steps in gluconeogenesis:
Malate + NAD+ <-> oxaloacetate + NADH
Glycerol-3-phosphate + NAD+ <-> DHAP + NADH
If the NAD+/NADH is too low → favor formation of both malate and glycerol-3-phosphate, which would prevent gluconeogenesis from occurring. Recall that when we are fasting, gluconeogenesis is one of the primary ways (in addition to glycogenolysis) we maintain our blood sugar, so if this is compromised by EtOH metabolism, particularly in a prolonged fasting state when we have used up our glycogen, we could be hypoglycemic.
Using your understanding of biochemistry, why might you have a fatty liver in prolonged EtOH consumption?
Recall EtOH metabolized to acetate, which can be converted to acetyl-CoA. Recall, too, that glycerol-3-phosphate is increased in states of high NADH.
Acetyl-CoA is the building block of fatty acids (recall that fatty acids are essentially long chains of acetyl-CoA strung together – you can remember this since when we oxidize/break down fatty acids, we get many acetyl-CoA molecules out), and so a preponderance of acetyl-CoA made from EtOH would provide plenty of material to make fatty acids.
Glycerol-3-phosphate is the 3-carbon backbone for triacylglycerol (AKA triglycerides). Since we are making not only more fatty acids, but also the backbone of triglycerides, these could accumulate in our liver.
What is the purpose of the urea cycle? What major organ deficit would you expect in a urea cycle disorder, and what is a proposed mechanism?
NH3 (ammonia) and NH4+ (ammonium) are produced as byproducts of amino acid breakdown/metabolism. Urea is synthesized to contain two of these molecules, and is inert – it is excreted by the kidneys.
If we can’t make urea (i.e. we have a urea cycle deficit) → neurologic problems. There are several proposed mechanisms, two of which are most biochemically relevant:
- Glutamate (a neurotransmitter, among other things) + NH3 → glutamine → deprive neurons of glutamate → inhibit neural transmission
- Oxaloacetate (OAA) + NH3 → aspartate. OAA is an intermediate of the TCA, thus if NH3 ↑ → OAA ↓ → TCA activity ↓ → NADH, FADH2 ↓ → electron transport activity ↓ → ATP production ↓ → neuronal dysfunction, as they are highly dependent on constant ATP production
What effect would an activating mutation in glutamate dehydrogenase have on blood ammonia levels?
Hyperammonemia
Recall glutamate dehydrogenase: glutamate → α-ketoglutarate + NH4+ (this NH4+ is then used in the first step of the urea cycle)
An activating mutation here would cause overproduction of NH4+ (and α-ketoglutarate, for that matter).
What effect would an activating mutation in glutamate dehydrogenase have on blood sugar levels?
Hypoglycemia
Recall glutamate dehydrogenase: glutamate → α-ketoglutarate + NH4+ (this is the same α-KG that is used in the TCA cycle)
α-KG is used in the TCA cycle → NADH / FADH2 ↑ → ATP ↑ → closure of ATP-gated K+ channels in pancreatic β cells → depolarization of β cells → insulin release → glucose uptake into cells ↑ → hypoglycemia
How is the urea cycle regulated? Why is this so clever?
N-acetyl glutamate (NAG) regulates the key regulated step of the urea cycle, carbamoyl phosphate synthase I (CPS I). NAG is composed of the two things you need in the urea cycle: acetyl-CoA (energy source) and glutamate (NH4+) source.
Why would an ornithine transcarbamoylase (OTC) deficiency lead to orotic aciduria?
OTC deficiency would lead to a build-up of carbamoyl phosphate in the mitochondria, which would lead into the cytosol where it would bypass CPS II and enter pyrimidine synthesis. Pyrimidine synthesis would continue until PRPP depletion, which would lead to a build-up of orotic acid, orotic acid requires PRPP to undergo the next step in pyrimidine synthesis.
Orotic aciduria (can’t convert orotic acid → UMP) vs. OTC deficiency – which would have megaloblastic anemia? Which would have hyperammonemia? Why?
OTC deficiency, which is a problem with the urea cycle, would have hyperammonemia, since it is a urea cycle deficit. If I can’t turn ammonia into urea, then it would accumulate.
Orotic aciduria, in which you have a problem with one of the steps in pyrimidine synthesis (converting orotic acid → UMP) → DNA synthesis problem → megaloblastic anemia.
How could a folic acid deficiency lead to megaloblastic anemia?
Straightforward: folate ↓ → tetrahydrofolate (THF) ↓ → purine AND pyrimidine synthesis ↓ (recall THF necessary for conversion of dUMP → dTMP via thymidylate synthase)
