Question

1) methotrexate is an inhibitor for the folate cycle which is important in both purine and pyrimidine synthesis. Where on each pathway does folate play a crucial role? How is this medication used as a chemotherapy?

2) Irritable bowel syndrome is a medical issue that results from a dysfunction in bile acid. Please explain normal pathways of bile acid in the body and then explain the dysfunctions related to bile acid in irritable bowel syndrome. Lastly how is this IBS medically managed?

3) A long distance runner is preparing to complete their first marathon. She is concerned about her nutrition before and after her race. What types of foods would be beneficial for an athlete prior to a long distance race? What pathways would be most active during the beginning of the race? At the end of the race? What would the effect be if she decided not to eat prior to the race or if she ate foods that were contraindicated?

4) How might a hypothetical disease causing the deacetylation of histones associated with the gene expressing malate dehydrogenase affect the respiratory chain? What symptoms might this disease cause and why?

Answer 1

1. Folate derivatives participate in the biosynthesis of both purines and pyrimidines. Formyl folate is required for two of the steps in the biosynthesis of inosine monophosphate, the precursor to GMP and AMP. Methylenetetrahydrofolate donates the C1 center required for the biosynthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). The conversion is catalyzed by thymidylate synthase. Methotrexate is an antimetabolite of the antifolate type. It is thought to affect cancer and rheumatoid arthritis by two different pathways. For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis.
2. The initial step in the classical pathway of hepatic synthesis of bile acids is the enzymatic addition of a 7α hydroxyl group by cholesterol 7α-hydroxylase (CYP7A1) forming 7α-hydroxycholesterol. This is then metabolised to 7α-hydroxy-4-cholesten-3-one. There are multiple steps in bile acid synthesis requiring 14 enzymes in all. These result in the junction between the first two steroid rings (A and B) being altered, making the molecule bent; in this process, the 3-hydroxyl is converted to the α orientation. The simplest 24-carbon bile acid has two hydroxyl groups at positions 3α and 7α. This is 3α,7α-dihydroxy-5β-cholan-24-oic acid, or, as more usually known, chenodeoxycholic acid. An alternative (acidic) pathway of bile acid synthesis is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1), expressed in liver, and also in macrophages and other tissues. CYP27A1 contributes significantly to total bile acid synthesis by catalyzing sterol side chain oxidation, after which cleavage of a three-carbon unit in the peroxisomes leads to formation of a C24 bile acid. Minor pathways initiated by 25-hydroxylase in the liver and 24-hydroxylase in the brain also may contribute to bile acid synthesis. 7α-hydroxylase (CYP7B1) generates oxysterols, which may be further converted in the liver to CDCA. According to Dr. Habba, one potential cause of the symptoms of functional diarrhea and diarrhea-predominant irritable bowel syndrome (IBS-D) is a dysfunctional gallbladder.Gallbladder dysfunction that leads to too much bile in the intestines (which in turn causes diarrhea) is known as the Habba syndrome. The Habba syndrome theory is based on excess bile in the gastrointestinal tract. Since it’s related to a dysfunctional gallbladder, treatment is focused on changing the bile acids to minimize their diarrheal effect.Dr. Habba and BAD researchers both suggest the use of acid binding agents such as: cholestyramine (Questran), colesevelam (WelChol), colestipol (Colestid)
3. Before any big race, build up energy reserves by loading on carbohydrates, starchy vegetables, fruits and lean protein for three days. Have a low-fat, high-carbohydrate and low-fibre meal about three hours before the race to prevent any indigestion, fatigue or stomach discomfort whilst running. Avoid heavy meals the day before the race and only eat familiar foods on the day itself. If athlete don't to eat immediately before running because it could lead to cramping or annoying side stitches. But running on an empty stomach may cause you to run out of energy and leave you feeling very fatigued during your runs.