*I ll try my best to incorporate the Slides in this Sheet; you don t need to study the slides if you study this sheet. Steroid Hormones Synthesis - The figure to the right is the Steroid nucleus, it has 17 carbons. - Has 4 rings, A, B, C are 6 membered rings and D is 5 membered. - Cholestrol is synthesized from it. - Note that you should memorize the numbers of Carbons, you ll need to know them when you study the enzymes - This is Cholesterol. Note the following: All steroid Hormone Classes are synthesized originally from cholestrol. It has a hydroxyl group on C3 Double bond between C5,C6 A Methyl group on C10 and C13. Those methyl groups are numbered 19, 18 respectively. It has a tail of 8 carbons on C17. 1
- There are the 5 classes of steroids, they re in this table, with their No. of Carbons, functions and where they re synthesized: - This is a Simple graph showing how each steroid Class is made. Note: Cholesterol is the Original Steroid for all the hormones. Removal of Carbons Changes Classes Estrogens are derived from Androgens. Cholesterol 27C Pregnenolone 21C Progestagens 21C Androgens 19C Mineralocorticoids 21C Glucocorticoids 21C Estrogens 18C 2
Now to the Actual Synthesis: - Steroids are hydroxylated by the Cytochrome P450 Monooxygenases. Example: - This enzyme is important in the synthesis of cholesterol from steroids, and the conversion of cholesterol into steroids hormones and bile Salts. - This reaction required NADPH and O2. NADPH is a reducing agent; it s used to reduce the 2 nd Oxygen from O2. - This is not the only function of the monooxygenase; it has many other functions, like in Drug metabolism. In drug metabolism Monooxygenases hydroxylate the drug, then the drug is bound to a molecule like glucose to help excrete it in the urine. This is how the reaction occurs: 3
1. Adrenodoxin is reduced by NADPH into its reduced form. 2. A Substrate (a steroid) binds Cytochrome P450 monooxygenase 3. Reduced Adrenodoxin donates an electron to a Ferric (Fe +3) iron group in the Cytochrome, it them becomes a Ferrous (Fe +2) iron group, which can bind oxygen. 4. O2 binds to the ferrous group. 5. Another Adrenodoxin gives another electron group 6. One of the oxygen atoms separate to form H2O. 7. The steroid leaves the Cytochrome, as a Hydroxylated Steroid. Pregnenolone Synthesis: - Pregnenolone synthesis also uses P450 enzyme. - When ACTH binds to the cell, it increases camp concentration, which facilitates this reaction. - Note how cholesterol is cleaved and carbon no. 20 has an aldehyde. - This reaction uses 3 NADPH molecules, 1 for the cleavage and 2 for the oxidation. 4
Progesterone Synthesis: - Progesterone is synthesized from Pregnenolone. - The hydroxyl group on C3 becomes an aldehyde, and the double bond between 5 and 6 is moved to 4 and 5. Synthesis of the remaining Steroid hormones: - The Remaining Steroids are synthesized from progesterone. - Before we take the exact reactions, there are a few things you should know. Hydroxylation can occur on C17,21, 11 C17 must be hydroxylated before C21. (how the enzyme functions) If C21 is hydroxylated before c17, then C17 cannot be hydroxylated. C11 can be Hydroxylated at any stage - Cortisol synthesis: By hydroxylation of C11, 17, 21 (circled OH groups) 5
- Aldosterone Synthesis: - By hydroxylation of progesterone at C21 and C11 (circles in image) to create Corticosterone. - Followed by oxidation of the 18C methyl group to an aldehyde group, to create Aldosterone. (Square in image). - Aldosterone is the only one with an aldehyde on C18 hence the name. Empty space right here: draw something or take notes in here 6
**This is the best I could fit the image in the page, if it s too small you can return to the slide to see it.(i know this looks a little complicated at first, but if you take time to understand it, you ll see that it s too complicated.) ** The names in the boxes are Enzyme names, the doctor said you should memorize them. - Note that you can get to 17-hydroxyprogesterone from Pregnenolone by 2 ways. - Note the differences between andostenedione, testosterone and their precursors. - Note that you can make testosterone from andostenedione. - The pathway of Cortisol and Aldosterone synthesis were explained before. 7
- Synthesis of andostenedione from Pregnenolone and Testosterone from progesterone use the same steps: 1. C17 hydroxylation 2. C20, C21 cleavage 3. C17 reduction to a Ketone group - There s a Hormone called DiHydroxyTestosterone, It s synthesized from testosterone by an enzyme called 5-Alpha-Reductase, which removes the double bond between C4 and C5 (Using NADPH). More potent than testosterone It s synthesized only in peripheral tissues. (not the testes) It is the reason why people consider testosterone a prohormone. - Estrogens: Synthesized from Androgens. Occurs by 2 Steps: 1. Loss of C19 angular methyl group 2. A ring becomes aromatic 8
Eicosanoids - considered Paracrine hormones - the precursor is Arachidonic acid (a fatty acid with 20 carbons and double bonds on C5,C8,C11,C14) - contain 3 classes: Prostaglandins (A,D,E,F,G,H,I) Leukotrienes Thromboxanes (A2,A4,E2,F2,I2) - produced in almost all tissues - have a wide range of responses - Very potent with short half life - Not stored (Synthesized and excreted when needed) - Some of their functions: (note that in the slides each function is listed under a different class, but the doctor said not to memorize what each class does, just know what the general functions of Eicosanoids are) Vasodilation & vasoconstriction (depends on which class) Inhibit & promote platelet aggregation (Depends on which class) Bronchoconstriction Increase camp in cells Smooth muscle contraction Increase lymphocyte proliferation Inhibit lymphocyte migration and aggregation 9
Note the following: ALL Thromboxanes (except A4) and prostaglandins have a ring Leukotrienes are NOT ringed The numbers in thromboxane types indicate the number of double bonds Synthesis of Eicosanoids: - Eicosanoids are derived from Arachidonic acid, which is found in membrane s phospholipids (usually on C2 of the glycerol molecule of phospholipids) - Arachidonic acid is derived from linoleic acid, which is a dietary fatty acid. - Phospholipase A2 cleaves the Arachidonic acid from the membrane Phospholipids, which frees it to be converted to any class of Eicosanoids. - Note that the cleavage by Phospholipase A2 is the rate limiting step in Eicosanoids synthesis - Cyclooxygenase & lipooxygenase work on Arachidonic acid to - Note that HETE (from the picture below) is hydroxy-eicosa-tetraenoic acid, it is a signaling molecule 10
The picture below describes the Cyclooxygenase pathway: 11
- Note that Eicosanoids can be made from other polyunsaturated fatty acids, not just Arachidonic acid - Those fatty acids must have 20 carbons; the no. of double bonds is not an issue. - Here s a table of fatty acids and the Eicosanoids they make: Fatty acid double bonds Eicosanoid Double bonds Arachidonic acid 4 PGE2,PGF2 2 Eicosapentaenoic acid 5 PGE3, PGF3 3 Eicosatrienoic acid 3 PGE1,PGF1 1 - Note that Eicosanoids produced from different fatty acids might have different actions. For example, Omega-3 fatty acids, which are found in fish, make Eicosanoids with 3 double bonds which inhibit platelet aggregation, while Eicosanoids with 2 double bonds promote platelet aggregation. Inhibition of prostaglandin synthesis: - By Steroidal anti-inflammatory drugs Those inhibit Phospholipase A2 - By nonsteroidal anti-inflammatory drugs Aspirin is an example By acytelation of Cyclooxygenase Binds irreversibly to the enzyme 12
Why is aspirin taken daily in small doses? In small doses, aspirin would bind to the Cyclooxygenase in platelets irreversibly, since the platelet is a semi-dead cell with no nucleus, it can t synthesize any Cyclooxygenase. And this mechanism helps inhibit platelet aggregation. - Cyclooxygenase exists in 2 forms: COX1: found in gastric mucosa, kidney and platelets, it s the constitutive form of the enzyme COX2: found in monocytes, macrophages and smooth muscles, it s the inducible form of the enzyme, the one induced in inflammation Done By: Owen Madaeen 13