{"id":1719,"date":"2020-08-14T17:32:40","date_gmt":"2020-08-14T17:32:40","guid":{"rendered":"https:\/\/meddists.com\/learn\/pre-clinical\/biochemistry\/biochemistry-of-the-metabolism\/carbohydrate-metabolism\/the-citric-acid-cycle\/"},"modified":"2021-09-13T10:56:49","modified_gmt":"2021-09-13T08:56:49","slug":"the-citric-acid-cycle","status":"publish","type":"page","link":"https:\/\/meddists.com\/learn\/pre-clinical\/biochemistry\/biochemistry-of-the-metabolism\/carbohydrate-metabolism\/the-citric-acid-cycle\/","title":{"rendered":"The citric acid cycle"},"content":{"rendered":"\n<p class=\"wp-block-paragraph\"><div class=\"intro\">The citric acid cycle:<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">takes place in the mitochondria<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">has 3 irreversible steps<\/p>\n\n\n\n<p class=\"wp-block-paragraph\">producing citrate, carbon dioxide, NADH and FADH<sub>2<\/sub><\/div><\/p>\n\n\n<span class=\"block-heading\" id=\"header_1\">\n<h4 class=\"wp-block-heading\" class=\"wp-block-heading\" class=\"title_collection title3\">Description<\/h4>\n<\/span><span class=\"block-content\" id=\"contents_1\">\n\n\n<p class=\"wp-block-paragraph\">The citric acid cycle takes place within the<strong>\u00a0mitochondria<\/strong>. <\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The major roles are:<\/p>\n\n\n\n<ul class=\"has-light-green-cyan-background-color has-background wp-block-list\"><li><strong>Production of NADH<\/strong> (3)<\/li><li><strong>Production of FADH<sub>2<\/sub><\/strong><\/li><li><strong>Production of CITRATE<\/strong><\/li><\/ul>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"alignright size-large is-resized\"><a href=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA.png\" target=\"_blank\" title=\"The citric acid cycle\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-1024x761.png\" alt=\"\" class=\"wp-image-6569\" width=\"512\" height=\"381\" srcset=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-1024x761.png 1024w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-300x223.png 300w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-768x571.png 768w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-1536x1142.png 1536w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA-2048x1522.png 2048w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA.png 1600w\" sizes=\"auto, (max-width: 512px) 100vw, 512px\" \/><\/a><figcaption><strong>Figure 1. Citric acid cycle schematic<\/strong><\/figcaption><\/figure><\/div>\n\n\n\n<p class=\"wp-block-paragraph\">For the production of&nbsp;<strong>citrate<\/strong>, a whole cycle is needed, which involves several enzymes.<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><em>The cycle is composed of several molecules, but it is easy to remember if we\u00a0<strong>count the number of carbon atoms<\/strong>, instead first all the chemical names.<\/em><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">The cycle is about to involve the previously produced\u00a0<strong>Acetyl-CoA (2C)<\/strong>\u00a0into\u00a0<strong>Citrate (C6)<\/strong>. It is easy to understand that we need a 4C molecule from somewhere \u2014 that\u2019s why the cycle\u00a0<strong>starts with Oxaloacetate (4C)<\/strong>\u00a0and together with the Acetyl-CoA,\u00a0<strong>citrate is formed<\/strong> (Figure 1).<\/p>\n\n\n\n<p class=\"wp-block-paragraph\"><em>During the cycle, the number of carbons is changing, but if the number is changing there has to be a change in the structure as well.<\/em><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">Therefore, we can assume that\u00a0<strong>all the irreversible reactions are catalyzed when the number of carbons is changing<\/strong>.\u00a0Within the cycle, there are three irreversible reactions (Figure 2).<\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter size-large is-resized\"><a href=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1.png\" target=\"_blank\" title=\"The citric acid cycle\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-1024x756.png\" alt=\"\" class=\"wp-image-6570\" width=\"768\" height=\"567\" srcset=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-1024x756.png 1024w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-300x222.png 300w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-768x567.png 768w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-1536x1134.png 1536w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1-2048x1512.png 2048w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA1.png 1600w\" sizes=\"auto, (max-width: 768px) 100vw, 768px\" \/><\/a><figcaption><strong>Figure 2<\/strong>. Irreversible reactions of TCA<\/figcaption><\/figure><\/div>\n\n\n<\/span><span class=\"block-heading\" id=\"header_2\">\n<h2 class=\"wp-block-heading\" class=\"wp-block-heading\" class=\"title_collection title1\">Reactions step by step<\/h2>\n<\/span><span class=\"block-content\" id=\"contents_2\">\n\n\n<div class=\"wp-block-image\"><figure class=\"alignleft size-large is-resized\"><a href=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2.png\" target=\"_blank\" title=\"The citric acid cycle\"><img loading=\"lazy\" decoding=\"async\" src=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-1024x811.png\" alt=\"\" class=\"wp-image-6571\" width=\"497\" height=\"394\" srcset=\"https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-1024x811.png 1024w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-300x237.png 300w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-768x608.png 768w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-1536x1216.png 1536w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2-2048x1621.png 2048w, https:\/\/meddists.com\/learn\/wp-content\/uploads\/2021\/09\/TCA2.png 1600w\" sizes=\"auto, (max-width: 497px) 100vw, 497px\" \/><\/a><figcaption><strong>Figure 2. Citric acid cycle <\/strong><\/figcaption><\/figure><\/div>\n\n\n\n<ol class=\"wp-block-list\"><li>The first step is the formation of the\u00a0<strong>citrate<\/strong>\u00a0itself, which is<strong>\u00a0irreversible<\/strong>\u00a0during hydrolysis of acetyl-CoA and oxaloacetate; the reaction is catalyzed by\u00a0<strong>citrate synthase.<\/strong>\u00a0<em>Citrate can develop further in the mitochondria, but it may also escalate into the cytosol, which promotes the transport of acetyl-CoA and thus the synthesis of fatty acids, and NADPH production.<\/em><br><\/li><li>Citrate is converted irreversibly to\u00a0<strong>isocitrate<\/strong>. The process is carried out in two steps, and the\u00a0<strong>aconitase<\/strong>\u00a0(Fe-S protein) catalyses the reaction which involves temporary dehydration, with cis-aconitate being intermediate.<br><\/li><li>The first dehydrogenation catalysed by\u00a0<strong>isocitrate\u00a0dehydrogenase<\/strong>, producing\u00a0<strong>CO<sub>2<\/sub><\/strong>\u00a0and\u00a0<strong>alpha-ketoglutarate<\/strong>\u00a0while reducing NAD<sup>+<\/sup>. <em>The reaction is an oxidative decarboxylation and is\u00a0<strong>irreversible<\/strong><\/em>.<em> Alpha-ketoglutarate may also be involved in other reactions or may continue in the citrate circle<\/em><br><\/li><li>The next step is<strong>\u00a0irreversible<\/strong>\u00a0too; the alpha-ketoglutarate is converted to\u00a0<strong>succinyl-CoA<\/strong>\u00a0using the\u00a0<strong>alpha-ketoglutarate dehydrogenase enzyme complex<\/strong>\u00a0\u2014 this is another oxidative decarboxylation whose energy generates a thioester bond. CoA-SH and NAD<sup>+<\/sup> are required for the reaction, resulting in\u00a0<strong>CO<sub>2<\/sub><\/strong>\u00a0formation. <em>The complex is composed of three enzymes: alpha-ketoglutarate dehydrogenase, dihydrolipoyl trans-succinylase and dihydrolipoyl reductase, and have the same cofactors as the pyruvate dehydrogenase complex. Here, there is no regulator kinase and phosphatase, and succinyl-CoA is an \u201cexit\u201d since it may be necessary for porphyrin synthesis<\/em>.<br><\/li><li><strong>Succinyl-CoA synthase<\/strong>: succinate, a succinyl derivative of the\u00a0<strong>succinyl-CoA<\/strong>\u00a0is produced while\u00a0<strong>GTP<\/strong>\u00a0is produced. This is substrate-level phosphorylation, producing a high energy bond. The process is reversible.<br><\/li><li>Succinate is converted to\u00a0<strong>fumarate<\/strong>\u00a0in a reversible reaction catalysed by\u00a0<strong>succinate dehydrogenase<\/strong>\u00a0linking the citrate circuit to the respiratory chain. The enzyme is a flavoprotein (Fe-S center) and is the only enzyme located inside the membrane, simultaneously being part of the terminal oxidation chain, Complex II. During the reaction, the FAD is reduced to FADH<sub>2<\/sub>, and hydrogens reduce the amount of ubiquinone.<br><\/li><li>The fumarate also produces L-<strong>malate<\/strong>\u00a0in a reversible reaction with the introduction of\u00a0<strong>fumarase<\/strong>.<br><\/li><li>The final step is also reversible, during which NAD<sup>+<\/sup>\u00a0reduction occurs as\u00a0<strong>malate dehydrogenase<\/strong>\u00a0converts L-malate to\u00a0<strong>oxaloacetate<\/strong>. <\/li><\/ol>\n\n\n\n<p class=\"has-light-green-cyan-background-color has-background wp-block-paragraph\"><strong>In the citrate cycle, the equation is:<\/strong>\u00a0<br><strong>acetyl-CoA + 3 NAD<sup>+<\/sup>\u00a0+ FAD + GDP + P<sub>i<\/sub> + 2 H<sub>2<\/sub>O = 2 CO<sub>2<\/sub>\u00a0+ 3 NADH + 3 H<sup>+<\/sup>\u00a0+ FADH<sub>2<\/sub>\u00a0+ GTP + CoA<\/strong><\/p>\n\n\n\n<p class=\"wp-block-paragraph\">An acetyl group is completely oxidized (2 CO<sub>2<\/sub>), into four pairs of hydrogen carriers (3 NAD + and 1 FAD is reduced), GTP is phosphorylated from GDP, so a total of 12 high potential bonds are formed (9 NADH from ATP, FADH<sub>2<\/sub>\u00a02 more ATP + from GTP). <\/p>\n\n\n\n<div class=\"wp-block-group\"><div class=\"wp-block-group__inner-container is-layout-flow wp-block-group-is-layout-flow\">\n<figure class=\"wp-block-table aligncenter is-style-stripes\"><table class=\"has-background\" style=\"background-color:#a9f6d7\"><tbody><tr><td><strong>Name of the enzyme <\/strong><\/td><td><\/td><td><strong>Function<\/strong><\/td><\/tr><tr><td><strong>CITRATE SYNTHASE<\/strong><\/td><td><\/td><td>Generates citrate from Acetyl-CoA + Oxalacetate<\/td><\/tr><tr><td><strong>ACONITASE<\/strong><\/td><td><\/td><td>Generates isocitrate from citrate<\/td><\/tr><tr><td><strong>ISOCITRATE DEHYDROGENASE<\/strong><\/td><td><\/td><td>Generates L-KG from isocitrate<\/td><\/tr><tr><td><strong>L-KG DEHYDROGENASE<\/strong><\/td><td><\/td><td>Generates Succinyl-CoA from L-KG<\/td><\/tr><tr><td><strong>SUCCINYL-COA SYNTHASE<\/strong><\/td><td><\/td><td>Generates succinate <\/td><\/tr><tr><td><strong>SUCCINATE DEHYDROGENASE<\/strong><\/td><td><\/td><td>Generates fumarate<\/td><\/tr><tr><td><strong>FUMARASE<\/strong><\/td><td><\/td><td>Generates malate<\/td><\/tr><tr><td><strong>MALATE DEHYDROGENASE<\/strong><\/td><td><\/td><td>Generates oxalacetate<\/td><\/tr><\/tbody><\/table><figcaption><strong>Table 1. Enzymes and their product<\/strong><\/figcaption><\/figure>\n<\/div><\/div>\n\n\n<\/span><span class=\"block-heading\" id=\"header_3\">\n<h2 class=\"wp-block-heading\" class=\"wp-block-heading\" class=\"title_collection title1\">Regulation<\/h2>\n<\/span><span class=\"block-content\" id=\"contents_3\">\n\n\n<p class=\"has-background wp-block-paragraph\" style=\"background-color:#f1f7fd\">The primary law is also true here, which means that the outcome (product) is going to inhibit the system and the intermediate is going to enhance it, but here it is hard to distinguish which one is the product.<\/p>\n\n\n\n<p class=\"has-background wp-block-paragraph\" style=\"background-color:#d4f8e9\"><strong>The primary regulatory points of the citrate cycle are influencing the three irreversible reaction-catalyzing enzymes<\/strong>.<\/p>\n\n\n\n<p class=\"has-background wp-block-paragraph\" style=\"background-color:#eeb5c3\">The formation of citrate is regulated by the activity of citrate synthase,\u00a0<br><strong>inhibited by ATP, NADH and fatty acid CoA<\/strong>.<\/p>\n\n\n\n<p class=\"has-background wp-block-paragraph\" style=\"background-color:#e9f4fd\">The catabolic determining step is the isocitrate dehydrogenase-catalyzed reaction, activated by ADP while \u00a0<strong>ATP, NADH, and succinyl-CoA<\/strong> are inhibiting.<\/p>\n\n\n\n<p class=\"has-background wp-block-paragraph\" style=\"background-color:#f3cbd5\">Alpha-ketoglutarate dehydrogenase is similar to PDH, but there is no kinase and phosphatase alone: it is inhibited by\u00a0<strong>ATP, NADH, succinyl CoA, and GTP<\/strong>.<\/p>\n\n\n\n<p class=\"has-light-green-cyan-background-color has-background wp-block-paragraph\">All three enzymes are stimulated by the increased concentration of Ca<sup>2+<\/sup>\u00a0ions (mainly in muscle tissue).<\/p>\n\n\n<\/span><span class=\"block-heading\" id=\"header_4\">\n<h2 class=\"wp-block-heading\" class=\"wp-block-heading\" class=\"title_collection title1\">References<\/h2>\n<\/span><span class=\"block-content\" id=\"contents_4\">\n\n\n<p class=\"wp-block-paragraph\">S<span style=\"font-size: revert; color: initial;\">nider MDS. Devlin\u2019s <strong>Textbook of Biochemistry with Clinical Correlations<\/strong>, the 8th Edition. John Wiley &amp; Sons, Incorporated, 2020; 2019.<\/span>  <\/p>\n<\/span><div id=\"the_titles\" style=\"display:none;\"><h4 class=\"wp-block-heading\" class=\"wp-block-heading\">Description<\/h4><h2 class=\"wp-block-heading\" class=\"wp-block-heading\">Reactions step by step<\/h2><h2 class=\"wp-block-heading\" class=\"wp-block-heading\">Regulation<\/h2><h2 class=\"wp-block-heading\" class=\"wp-block-heading\">References<\/h2><\/div>","protected":false},"excerpt":{"rendered":"<p>Description The citric acid cycle takes place within the\u00a0mitochondria. The major roles are: Production of NADH (3) Production of FADH2 Production of CITRATE For the production of&nbsp;citrate, a whole cycle is needed, which involves several enzymes. The cycle is composed of several molecules, but it is easy to remember if we\u00a0count the number of carbon [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":1711,"menu_order":2,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":""},"class_list":["post-1719","page","type-page","status-publish","hentry"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>The citric acid cycle &#8211; Meddists<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/meddists.com\/learn\/pre-clinical\/biochemistry\/biochemistry-of-the-metabolism\/carbohydrate-metabolism\/the-citric-acid-cycle\/\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"5 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/meddists.com\\\/learn\\\/pre-clinical\\\/biochemistry\\\/biochemistry-of-the-metabolism\\\/carbohydrate-metabolism\\\/the-citric-acid-cycle\\\/\",\"url\":\"https:\\\/\\\/meddists.com\\\/learn\\\/pre-clinical\\\/biochemistry\\\/biochemistry-of-the-metabolism\\\/carbohydrate-metabolism\\\/the-citric-acid-cycle\\\/\",\"name\":\"The citric acid cycle &#8211; 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