User:Gruskyd/sandbox

Citric acid cycle article notes: -Overview does not contain citations or references to any particular source material. Although much of this information might be considered general information, and therefore not necessitate a citation, it would be better if the material covered were cited to at least a secondary source. Some areas of this section in particular seem to warrant a citation. -More of a clarification note, but it seems as though several intermediates are listed under the steps section without the proper notification that these are intermediates. It would be more clear if they were noted as such -Would be good to see a citation on how NADH can be used for ATP creation. (Why does NADH produce ATP? Why does it produce the amount that it does?) -The regulation section contains a lot of information that does not have citations. Even though this is mostly overview information, it would be good to put in a citation to at least a textbook. For instance, the first paragraph contains a large number of declarative statements on how regulation of the citric acid cycle occurs, but it is unclear if those statements come from an particular source. Although these statements seem to be true, if may be helpful to cite them. -Sentence structure in Acetyl-CoA portion of major metabolic pathways converging to TCA section is slightly strange.

Pentose Phosphate Pathway article notes: -Outcome section lacks a number of citations, although this seems to be noted already -Similary, the regulation section also lacks citations

Sources for Ketogenesis article:

Pain-Free Biochemistry - http://site.ebrary.com/lib/reed/reader.action?docID=10361167

Regulation of Ketone Body Metabolism and the Role of PPARα - http://www.mdpi.com/1422-0067/17/12/2093/htm

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme - http://www.biochemj.org/content/ppbiochemj/338/3/569.full.pdf

http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1520-7560(199911/12)15:6%3C412::AID-DMRR72%3E3.0.CO;2-8/full (Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes)

Principles of Biochemistry, 6th edition (Lehninger)

Editing plans for Ketogenesis article: For the most part, I intend to expand on the existing sections of the article. In particular, it seems as though there is a great deal of available information on the pathology and regulation of ketogenesis, so I hope to focus primarily on those aspects of the article. I also hope to expand on the ketone body section as well, although only to some extent, as there already is a wikipedia article dedicated to ketone bodies. For now I only have a handful of sources, but since a few of them are fairly large, I think it would be best to take the time to work through these first before figuring out what other information or sources I need to improve the article. For the most part these sources compile numerous research articles, so I think that they should be relatively reliable.

Much of the below article comes from the original wikipedia article on Ketogenesis. This has not yet been changed, so in order to see the original article without my edits, use the link. I have brought it into the sandbox so that it can be worked upon easily. Alterations have been made to a few parts in the production, ketone bodies, regulation and pathology sections. My Changes have been bolded.

Ketogenesis article draft

Ketogenesis is the biochemical process by which organisms produce a group of substances collectively known as ketone bodies by the breakdown of fatty acids and ketogenic amino acids. This process supplies energy to certain organs (particularly the brain) under circumstances such as fasting, but insufficient ketogenesis can cause hypoglycemia and excessive production of ketone bodies leads to a dangerous state known as ketoacidosis.

Production

Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis can occur in response to an unavailability of blood glucose, such as during fasting. Other cells are capable of carrying out ketogenesis, but they are not as effective at doing so. Ketogenesis occurs constantly in a healthy individual.

Ketogenesis takes place in the setting of low glucose levels in the blood, after exhaustion of other cellular carbohydrate stores, such as glycogen. It can also take place when there is insufficient insulin (e.g. in type 1 (but not 2) diabetes), particularly during periods of "ketogenic stress" such as intercurrent illness.

The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Under normal conditions, acetyl-CoA is further oxidized by the citric acid cycle (TCA/Krebs cycle) and then by the mitochondrial electron transport chain to release energy. However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA). Furthermore, since there is only a limited amount of coenzyme A in the liver the production of ketogenesis allows some of the conenzyme to be freed to continue fatty-acid β-oxidation. Depletion of glucose and oxaloacetate can be triggered by fasting, vigorous exercise, high-fat diets or other medical conditions, all of which enhance ketone production. Deaminated amino acids that are ketogenic, such as leucine, also feed TCA cycle, forming acetoacetate & ACoA and thereby produce ketones. Besides its role in the synthesis of ketone bodies, HMG-CoA is also an intermediate in the synthesis of cholesterol, but the steps are compartmentalised. Ketogenesis occurs in the mitochondria, whereas cholesterol synthesis occurs in the cytosol, hence both the processes are independently regulated.

Ketone bodies

The three ketone bodies, each synthesized from acetyl-CoA molecules, are:

• Acetoacetate, which can be converted by the liver into β-hydroxybutyrate, or spontaneously turn into acetone
• Acetone, which is generated through the decarboxylation of acetoacetate, either spontaneously or through the enzyme acetoacetate decarboxylase. It can then be further metabolized either by CYP2E1 into hydroxyacetone (acetol) and then via propylene glycol to pyruvate, lactate and acetate (usable for energy) and propionaldehyde, or via methylglyoxal to pyruvate and lactate.
• β-hydroxybutyrate (not technically a ketone according to IUPAC nomenclature) is generated through the action of the enzyme D-β-hydroxybutyrate dehydrogenase on acetoacetate.

β-Hydroxybutyrate is the most abundant ketone bodies, followed by acetoacetate and finally acetone. β-Hydroxybutyrate and Acetoacetate can pass through membranes easily, and are therefore a source of energy for the brain, which cannot directly metabolize fatty acids. The brain receives 60-70% of its required energy from ketone bodies when blood glucose levels are low. These bodies are transported into the brain by monocarboxylate transporters 1 and 2 . Therefore, ketone bodies are a way to move energy from the liver to other cells. The liver does not have the critical enzyme, succinyl CoA transferase, to process ketone bodies, and therefore cannot undergo ketolysis. The result is that the liver only produces ketone bodies, but does not use them as well.

Regulation

Ketogenesis may or may not occur, depending on levels of available carbohydrates in the cell or body. This is closely related to the paths of acetyl-CoA:

• When the body has ample carbohydrates available as energy source, glucose is completely oxidized to CO₂; acetyl-CoA is formed as an intermediate in this process, first entering the citric acid cycle followed by complete conversion of its chemical energy to ATP in oxidative phosphorylation.
• When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored in the form of glycogen or, upon citrate excess, as fatty acids. (CoA is also recycled here.)
• When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.

Insulin and Glucagon are key regulating hormones of ketogenesis. Both hormones regulate Hormone sensitive lipase and acetyl-CoA carboxylase. Hormone sensitive lipase produces diglycerides from triglycerides, preparing these molecules for fatty acid synthesis. Acetyl-CoA carboxylase catalyzes the production of malonyl-CoA from acetyl-CoA. Malonyl-CoA reduces the activity of carnitine palmitoyltransferase 1, an enzyme that works to bring fatty acids into the mitochondria for β-oxidation. Insulin inhibits hormone sensitive lipase and activates acetyl-CoA carboxylase, thereby reducing the amount of starting materials for fatty acids synthesis and inhibiting their capacity to enter the mitochondria. Glucagon activates hormone sensitive lipase and inhibits acetyl-CoA carboxylase, thereby stimulating ketone body production, and making passage into the mitochondria for β-oxidation easier. Additionally, HMG-CoA is inhibited by insulin, reducing ketone body production. Similarly, cortisol, catecholamines, epinephrine, norepinephrine and thyroid hormones can increase the amount of ketone bodies produced as they increase the concentration of fatty acids available for β-oxidation.

Peroxisome Proliferator Activated Receptors (PPARα's), also have the ability to regulate ketogenesis, as they have some control over a number of genes involved in Ketogenesis. For example, Monocarboxylate transporter 1, which is involved in transporting ketone bodies over membranes, is regulated by PPARα, thus affecting ketone body transportation into the brain.  Carnitine palmitoyltransferase is also regulated by PPARα, which can affect fatty acid transportation into the mitochondria.

Pathology

Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis. Ketoacidosis is known to occur in untreated type I diabetes (see diabetic ketoacidosis) and in alcoholics after prolonged binge-drinking without intake of sufficient carbohydrates (see alcoholic ketoacidosis).

Ketogenesis can be ineffective in people with beta oxidation defects.

Individuals with diabetes mellitus can experience overproduction of ketone bodies due to a lack of insulin. Without insulin to help extract glucose from the blood, tissues the levels of malonyl-CoA are reduced, and it becomes easier for fatty acids to be transported into mitochondria, causing the accumulation of excess acetyl-CoA. The accumulation of acetyl-CoA in turn produces excess ketone bodies through ketogenesis. The result is a rate of ketone production higher than the rate of ketone disposal, and an increase in body pH.

There are some health benefits to ketone bodies and ketogenesis as well. It has been suggested that a low-carb, high fat ketogenic diet can be used to help treat epilepsia in children. Additionally, ketone bodies can be anti-inflamatory. Some kinds of cancer cells are unable to use ketone bodies, as they do not have the necessary enzymes to engage in ketolysis. It has been proposed that actively engage in behaviors that promote ketogenesis and could help manage the effects of some cancers.

See also

• Ketone bodies
• Fatty acid metabolism
• Ketosis
• Ketogenic diet

External links

• Fat metabolism at University of South Australia
• James Baggott. (1998) Synthesis and Utilization of Ketone Bodies at University of Utah Retrieved 23 May 2005.
• Musa-Veloso K, Likhodii SS, Cunnane SC (1 July 2002). "Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals". Am. J. Clin. Nutr. 76 (1): 65–70. PMID 12081817.
• Richard A. Paselk. (2001) Fat Metabolism 2: Ketone Bodies at Humboldt State University Retrieved 23 May 2005.