{"id":537,"date":"2016-09-28T03:44:54","date_gmt":"2016-09-28T08:44:54","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=537"},"modified":"2016-09-28T03:44:54","modified_gmt":"2016-09-28T08:44:54","slug":"anaplerotic-molecules-current-and-future","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/anaplerotic-molecules-current-and-future\/","title":{"rendered":"Anaplerotic molecules: Current and future"},"content":{"rendered":"

The concept of anaplerosis<\/b><\/strong>
\nThe oxidation of acetyl groups in the citric acid cycle (CAC)\u00a0involves eight reactions, which (i) convert the two carbons of\u00a0acetyl to CO2<\/sub>, and (ii) regenerate the acceptor of the acetyl\u00a0group, i.e., oxaloacetate. When the only source of carbon entering the CAC is acetyl-CoA, the net fluxes through the eight\u00a0reactions of the cycle are identical, although most of the reactions are reversible in intact cells (except citrate synthase\u00a0and \u03b1<\/i><\/em>-ketoglutarate dehydrogenase). The size of the total\u00a0pool of the eight CAC intermediates (1\u20132 \u03bc<\/i><\/em>mol\/g) is small\u00a0compared to the throughput of the cycle (1\u20132\u00a0\u03bc<\/i><\/em>mol acetyl\/g\u00a0per min). This is why the eight intermediates are referred to\u00a0as \u2018catalytic intermediates\u2019 of the CAC. Figure 1 illustrates\u00a0the large differences between the sizes of the pools of individual intermediates. As a consequence, the turnover of these\u00a0pools varies greatly: 5\u201310 times\/min for citrate, and 100\u2013200\u00a0times\/min for oxaloacetate.<\/p>\n

Although the reactions of the CAC provide 100% recovery\u00a0of the catalytic intermediates, there is a physiological \u2018leakage\u2019 of intermediates through the mitochondrial membranes\u00a0and the cell membranes, often referred to as \u2018cataplerosis\u2019.\u00a0Although the word \u2018cataplerosis\u2019 is, sensu stricto<\/i><\/em>, a misnomer, it is used extensively in the recent literature. The rate\u00a0of physiological cataplerosis in the normal heart is estimated\u00a0at 1\u20132% of the total pool per min. If the leakage of catalytic\u00a0intermediates were not balanced by the re-filling reactions of\u00a0anaplerosis, the flux through the CAC and the regeneration\u00a0of ATP could not be sustained. Therefore, the maintenance\u00a0of adequate pools of CAC intermediates is a conditio sine<\/i><\/em>\u00a0<\/i><\/em>qua non <\/i><\/em>of cell survival and homeostasis. Indeed, the mechanical performance of isolated rat hearts decreases rapidly\u00a0when the perfusate contains only precursors of acetyl-CoA,\u00a0i.e., acetate or acetoacetate. Recovery of cardiac mechanical\u00a0performance follows the addition of an anaplerotic substrate\u00a0(pyruvate, propionylcarnitine) to the perfusate.<\/p>\n

Pyruvate is anaplerotic via pyruvate carboxylase and\/or malic enzyme. Glutamate<\/a>, and its abundant\u00a0precursor glutamine, are converted to \u03b1-ketoglutarate by\u00a0reactions catalysed by glutamate dehydrogenase and\/or\u00a0aminotransferases. Numerous precursors of propionyl-CoA\u00a0(odd-chain fatty acids, propionylcarnitine, C5-ketone bodies)\u00a0form succinyl-CoA via methylmalonyl-CoA. Lastly, aspartate derived from protein degradation forms oxaloacetate by\u00a0transamination reaction, or fumarate via the reactions of the\u00a0purine nucleotide cycle and of the urea\u00a0cycle.<\/p>\n

There is good evidence that the total concentration of\u00a0CAC intermediates can vary by up to a few fold during\u00a0transitions between metabolic situations. This is observed\u00a0(i) in muscle during the transition from rest to exercise,\u00a0(ii) in heart and liver upon supply of anaplerotic substrates, and (iii) in liver during the transition\u00a0from fasting to feeding. However,\u00a0in a given metabolic situation, anaplerotic flux in excess of\u00a0physiological leakage must be balanced by a corresponding\u00a0cataplerotic flux. For example, in the liver, gluconeogenic\u00a0carbons of pyruvate and propionyl-CoA, which enter the\u00a0CAC via pyruvate carboxylase and methylmalonyl-CoA mutase, leave the cycle via phosphoenolpyruvate (PEP) carboxykinase. In the perfused rat heart, anaplerosis from high\u00a0concentrations of propionate is balanced by an efflux of\u00a0malate. As anaplerotic molecules pass through reactions of\u00a0the CAC, there is no net CO2<\/sub>\u00a0production, except from C1\u00a0of glutamine\/glutamate. Thus, except for the latter, the production of labelled CO2<\/sub>\u00a0from a labelled anaplerotic substrate reflects not net oxidation of the substrate but isotopic\u00a0exchanges in the CAC. This is true unless additional reactions form labelled mitochondrial acetyl-CoA from the\u00a0anaplerotic substrate, for example via malic enzyme+ pyruvate dehydrogenase, or PEP carboxykinase and pyruvate\u00a0dehydrogenase.<\/p>\n

In addition to maintaining the pool of CAC intermediates, anaplerotic and cataplerotic reactions play a central\u00a0role in gluconeogenesis from amino acids, lactate and pyruvate, as well as in the urea cycle. In the brain, anaplerotic\u00a0reactions contribute to the regulation of the metabolism\u00a0of neurotransmitters. Also, anaplerotic glutamine synthesis is coupled to removal of nitrogen from the brain in\u00a0hyperammonaemia. Lastly, anaplerosis\u00a0appears to play an important role in the secretion of insulin by pancreatic \u03b2-cells. The\u00a0stimulation of anaplerosis by physiological fuel secretagogues is accompanied by a corresponding cataplerosis\u00a0that transfers CAC intermediates to the extramitochondrial\u00a0space. The transferred molecules could act as secretagogues\u00a0or as exporters of equivalents of NADPH, acetyl-CoA or\u00a0malonyl-CoA.<\/p>\n

There is good evidence that a number of pathological conditions could benefit from anaplerotic therapy. Conditions\u00a0associated with reperfusion injury (myocardial infarction,\u00a0stroke, organ transplantation) are associated with damage to\u00a0cell membranes and possible decrease in the pools of some\u00a0CAC intermediates. Applications of anaplerotic therapy to\u00a0the dietary treatment of some inherited metabolic diseases are\u00a0extensively discussed in a paper published in this issue. Note that, when considering anaplerotic\u00a0therapy, it is impossible in most cases to demonstrate either\u00a0a decrease in the concentration of CAC intermediates in tissues or\u00a0an excessive leakage of intermediates from a tissue.\u00a0The latter might be inferred from evidence of the leakage\u00a0of large molecules such as creatine kinase during myocardial infarction or rhabdomyolysis. Still, one\u00a0cannot assess whether the concentration of oxaloacetate, the\u00a0acetyl-CoA acceptor and least abundant CAC intermediate,\u00a0is sufficient to allow proper CAC flux and energy production. In most cases, evidence of the need for anaplerotic therapy can only be inferred a posteriori <\/i><\/em>from the improvement\u00a0of cardiac function, muscle\u00a0strength, or neurological status.<\/p>\n

 <\/p>\n

Reference\uff1a<\/p>\n

Henri Brunengraber,\u00a0Charles R. Roe. J Inherit Metab Dis (2006) 29:327\u2013331<\/p>\n","protected":false},"excerpt":{"rendered":"

The concept of anaplerosis The oxidation of acetyl groups in the citric acid cycle (CAC)\u00a0involves eight reactions, which (i) convert the two carbons of\u00a0acetyl to CO2, and (ii) regenerate the […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[324,321,322],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/537"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=537"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/537\/revisions"}],"predecessor-version":[{"id":538,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/537\/revisions\/538"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=537"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=537"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=537"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}