View source for Citric acid cycle/ja

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[[File:Citric acid cycle with aconitate 2.svg|thumb|upright=2|クエン酸サイクルの概要]]
'''クエン酸サイクル'''（'''Citric acid cycle'''）は、'''Krebs cycle''', '''Szent-Györgyi-Krebs cycle''' '''TCA cycle (tricarboxylic acid cycle)'''とも呼ばれ、 [[carbohydrate/ja|炭水化物]]、[[fat/ja|脂質]]、[[protein/ja|タンパク質]]に由来する[[acetyl-CoA/ja|アセチル-CoA]]の[[Redox|oxidation/ja|酸化還元]]によって[[nutrient/ja|栄養素]]に蓄積されたエネルギーを放出する一連の[[chemical reaction/ja|生化学反応]]である。放出された化学エネルギーは[[Adenosine triphosphate/ja|ATP]]の形で利用できる。[[:en:Hans Krebs (biochemist)|クレブス]]サイクルは、[[anaerobic respiration/ja|嫌気性呼吸]]または[[aerobic respiration/ja|好気性呼吸]]によってエネルギーを生成するために、[[Cellular respiration/ja|呼吸]]を行う[[organism/ja|生物]]（[[Fermentation/ja|発酵]]を行う生物とは異なる）によって使用される。さらに、このサイクルは特定の[[amino acid/ja|アミノ酸]]の[[precursor (chemistry)/ja|前駆体]]、および[[reducing agent/ja|還元剤]]を供給する。[[nicotinamide adenine dinucleotide/ja|NADH]]を供給する。多くの[[Metabolic pathway/ja|生化学的経路]]における中心的な重要性は、それが[[metabolism/ja|代謝]]の最も初期の構成要素の一つであったことを示唆している。クエン酸サイクルは「サイクル」と呼ばれているが、[[metabolite/ja|代謝物]]が1つの特定の経路をたどる必要はない。

この代謝経路の名前は、消費された[[citric acid/ja|クエン酸]]（[[tricarboxylic acid/ja|トリカルボン酸]]の一種で、生物学的pHではイオン化型が優勢であるため、しばしばクエン酸塩と呼ばれる）に由来し、サイクルを完成させるためにこの一連の反応によって再生される。サイクルは酢酸（[[acetyl-CoA/ja|アセチル-CoA]]の形）と[[water/ja|水]]を消費し、NAD<sup>+</sup>をNADHに還元し、二酸化炭素を放出する。クエン酸サイクルによって生成されたNADHは[[oxidative phosphorylation/ja|酸化的リン酸化]]（電子輸送）経路に供給される。これら2つの密接に結びついた経路の正味の結果は、[[nutrient/ja|栄養素]]を酸化して[[adenosine triphosphate/ja|ATP]]の形で使用可能な化学エネルギーを生成することである。

[[eukaryotic/ja|真核生物]]細胞では、クエン酸サイクルは[[mitochondrion/ja|ミトコンドリア]]のマトリックスで起こる。ミトコンドリアを持たない細菌などの[[原核生物]]細胞では、クエン酸サイクルの反応シーケンスは細胞質で行われ、[[Chemiosmosis/ja|ATP生成]]のためのプロトン勾配は[[mitochondrion/ja|ミトコンドリオン]]の内膜ではなく細胞表面（[[cell membrane/ja|漿膜]]）を横切る。

1つのピルビン酸分子（解糖からの）に対して、クエン酸サイクルからのエネルギー含有化合物の全体的な収量は、3つのNADH、1つの[[Flavin adenine dinucleotide/ja|FADH<sub>2</sub>]]、および1つの[[guanosine triphosphate/ja|GTP]]である。

== 発見 ==
{{Anchor|Discovery}}
クエン酸サイクルの構成要素と反応のいくつかは、1930年代に[[:en:Albert Szent-Györgyi|アルバート・ツェント＝ギョルギ]]の研究によって確立された。彼は1937年、サイクルの構成要素である[[fumaric acid/ja|フマル酸]]に関する発見で[[:en:Nobel Prize in Physiology or Medicine|ノーベル生理学・医学賞]]を受賞した。彼はこの発見を、ハトの胸筋の研究によって行った。この組織はラタピーミルで分解され、水溶液中で放出された後も酸化能力を維持するため、ハトの胸筋は酸化反応の研究に非常に適していた。クエン酸サイクル自体は、1937年に[[:en:University of Sheffield|シェフィールド大学]]に在籍していた[[:en:Hans Adolf Krebs|ハンス・アドルフ・クレブス]]と[[:en:William Arthur Johnson (biochemist)|ウィリアム・アーサー・ジョンソン]]によって最終的に同定され、この功績で前者は1953年に[[:en:Nobel Prize for Physiology or Medicine|ノーベル生理学・医学賞]]を受賞した。

<div class="mw-translate-fuzzy">
== 概要 ==
{{Anchor|Overview}}
[[File:Acetyl-CoA-2D_colored.svg|thumb|upright=1.6|アセチル-CoAの構造図： 左側の青い部分が[[Acetyl/ja|アセチル基]]、黒い部分が[[coenzyme A/ja|補酵素A]]である。]]
クエン酸サイクルは、[[carbohydrate/ja|炭水化物]]、[[fat/ja|脂肪]]、[[protein/ja|タンパク質]]をつなぐ[[metabolic pathwary/ja|代謝経路]]である。このサイクルの[[Chemical reaction/ja|反応]]は8つの[[enzymes/ja|酵素]]によって行われ、[[acetate/ja|酢酸]]（炭素数2の分子）をアセチル-CoAの形で完全に酸化し、それぞれ2分子の二酸化炭素と水にする。糖、脂肪、タンパク質の[[catabolism]/ja|異化]]によって、炭素数2の有機生成物アセチル-CoAが生成され、クエン酸サイクルに入る。サイクルの反応はまた、3当量の[[nicotinamide adenine dinucleotide/ja|ニコチンアミドアデニンジヌクレオチド]]（NAD<sup>+</sup>）を3当量の還元型[[Nicotinamide adenine dinucleotide/ja|NAD<sup>+</sup>]]（NADH）に変換する、 [[flavin adenine dinucleotide/ja|フラビンアデニンジヌクレオチド]]（FAD）を1当量の[[Flavin adenine dinucleotide/ja|FADH<sub>2</sub>]]に、[[guanosine diphosphate/ja|グアノシン二リン酸]]（GDP）と無機[[phosphate/ja|リン酸]]（P<sub>i</sub>）をそれぞれ1当量の[[guanosine triphosphate/ja|グアノシン三リン酸]]（GTP）に変換する。クエン酸サイクルによって生成されたNADHとFADH<sub>2</sub>は、[[oxidative phosphorylation/ja|酸化的リン酸化]]経路によってエネルギー豊富なATPを生成するために使われる。
</div>

アセチル-CoAの主な供給源のひとつは、[[glycolysis/ja|解糖]]による糖の分解で、[[pyruvic acid/ja|ピルビン酸]]が得られ、それが[[pyruvate dehydrogenase complex/ja|ピルビン酸デヒドロゲナーゼ複合体]]によって脱炭酸され、以下の反応スキームに従ってアセチル-CoAを生成する：

{{block indent|{{underset|pyruvate|2=CH<sub>3</sub>C(=O)C(=O)O<sup>−</sup>}} + [[Coenzyme A/ja|HSCoA]] + NAD<sup>+</sup> → {{underset|acetyl-CoA|2=CH<sub>3</sub>C(=O)SCoA}} + NADH + CO<sub>2</sub>}}

この反応の産物であるアセチル-CoAはクエン酸サイクルの出発点である。[[Acetyl-CoA carboxylase/ja|アセチル-CoA]]は[[fatty acid/ja|脂肪酸]]の酸化からも得られる。以下にサイクルの概略を示す：
* [[citric acid/ja|クエン酸]]サイクルは、アセチル-CoAから炭素数4のアクセプター化合物（オキサロ酢酸）に炭素数2の[[acetyl/ja|アセチル]]基が移動し、炭素数6の化合物（クエン酸）が形成されることから始まる。
* クエン酸塩はその後一連の化学変化を経て、2つの[[carboxyl/ja|カルボキシル]]基を[[Carbon dioxide/ja|CO<sub>2</sub>]]として失う。CO<sub>2</sub>として失われた炭素は、アセチル-CoAから直接ではなく、オキサロ酢酸に由来する。アセチル-CoAから供与された炭素は、クエン酸サイクルの最初のターンの後、オキサロ酢酸炭素骨格の一部となる。CO<sub>2</sub>としてアセチル-CoAから供与された炭素が失われるには、クエン酸サイクルを何回か回す必要がある。しかし、クエン酸サイクルは[[anabolic/ja|同化]]の役割を担っているため、多くのクエン酸サイクル中間体は他の分子の[[biosynthesis/ja|生合成]]の前駆体としても使われるため、失われることはないかもしれない。
* サイクルの酸化的ステップによって利用可能になった電子のほとんどはNAD<sup>+</sup>に移動し、NADHを形成する。クエン酸サイクルに入るアセチル基1つにつき、3分子のNADHが生成される。クエン酸サイクルには、ミトコンドリアにおける一連の酸化還元反応が含まれる。
* さらに、コハク酸酸化ステップからの電子は、まずコハク酸デヒドロゲナーゼの[[FAD/ja|FAD]]補因子に移動し、FADH<sub>2</sub>に還元される、 そして最終的には[[Mitochondrion/ja|ミトコンドリア膜]]中の[[ubiquinone/ja|ユビキノン]]（Q）に移動し、[[Complex III/ja|複合体III]]のレベルで[[Electron transport chain/ja|電子伝達鎖]]の基質である[[ubiquinol/ja|ユビキノール]]（QH<sub>2</sub>）に還元される。
* クエン酸サイクルでNADHとFADH<sub>2</sub>が生成されるごとに、酸化的[[phosphorylation/ja|リン酸化]]でそれぞれ2.5と1.5個のATP分子が生成される。
* 各サイクルの終わりには、炭素数4の[[Oxaloacetic acid/ja|オキサロ酢酸]]が再生され、サイクルが継続される。

<div class="mw-translate-fuzzy">
== ステップ ==
{{Anchor|Steps}}
クエン酸サイクルには、以下に概説する10の基本ステップがある。このサイクルには、表のステップ0から入る[[acetyl-CoA/ja|アセチル-CoA]]の形で新しい炭素が継続的に供給される。
{| class="wikitable"
!
!反応タイプ
!基板
!酵素
!生成物
!コメント
|-
|{{nowrap|0 / 10}}
|[[Aldol condensation/ja]]
|[[Oxaloacetic acid/ja|オキサロ酢酸]] + [[Acetyl CoA/ja|アセチルCoA]] + H<sub>2</sub>O
|[[Citrate synthase/ja]]
|[[Citric acid/ja|クエン酸塩]] + [[Coenzyme A/ja|CoA-SH]]
|不可逆的に、4Cの[[Oxaloacetic acid/ja|オキサロ酢酸]]を6Cの分子に拡張する
|-
|1
| [[Dehydration reaction/ja|脱水症状]]
|[[Citrate/ja]]
| rowspan="2" |[[Aconitase/ja]]
|''[[Cis–trans isomerism/ja|cis]]''-[[Aconitic acid|アコニット]] + H<sub>2</sub>O
|rowspan=2|可逆 [[Isomerization/ja|異性化]]
|-
|2
|[[Hydration reaction/ja|水分補給]]
|[[Aconitate/ja|''cis''-アコニット]] + H<sub>2</sub>O
|[[Isocitric acid/ja|イソクエン酸塩]]
|-
|3
|[[Oxidation/ja]]
|[[Isocitrate/ja]] + [[Nicotinamide adenine dinucleotide/ja|NAD]]<sup>+</sup>
| rowspan="2" |[[Isocitrate dehydrogenase/ja]]
|[[Oxalosuccinic acid/ja|オキサロコハク酸塩]] + [[Nicotinamide adenine dinucleotide/ja|NADH + H <sup>+</sup>]]
|[[NADH/ja|NADH]]生成 (2.5ATPに相当する)
|-
|4
|[[Decarboxylation/ja]]
|[[Oxalosuccinate/ja]]
|[[alpha-Ketoglutaric acid/ja|α-ケトグルタル酸]] + CO<sub>2</sub>
|律速段階となる不可逆的な段階では、5C分子が生成される。
|-
|5
|酸化的<br />[[decarboxylation/ja|脱炭酸]]
|[[alpha-Ketoglutaric acid/ja|α-ケトグルタル酸]] + NAD<sup>+</sup> + CoA-SH
|[[Alpha-ketoglutarate dehydrogenase/ja|α-ケトグルタル酸<br />デヒドロゲナーゼ]], [[Thiamine pyrophosphate/ja]], [[Lipoic acid/ja]], Mg++,トランスサクシニターゼ
|[[Succinyl-CoA/ja]] + [[Nicotinamide adenine dinucleotide/ja|NADH + H <sup>+</sup>]] + CO<sub>2</sub>
|不可逆的な段階で[[Nicotinamide adenine dinucleotide/ja|NADH]]を生成 (ATP2.5分）、4C鎖を再生する（CoAは除く）。
|-
|6
|[[substrate-level phosphorylation/ja|基質レベルの<br />リン酸化]]
|[[Succinyl-CoA/ja]] + [[Guanosine diphosphate/ja|GDP]] + [[Inorganic phosphate/ja|P<sub>i</sub>]]
|[[Succinyl coenzyme A synthetase/ja|スクシニル-CoA合成酵素]]
|[[Succinic acid/ja|コハク酸塩]] + CoA-SH + [[Guanosine triphosphate/ja|GTP]]
|あるいは、 GDP→GTPの代わりに[[adenosine diphosphate/ja|ADP]]→[[adenosine triphosphate/ja|ATP]]で1ATP生成される。<br /> [[Guanosine diphosphate/ja|GDP]]+[[Inorganic phosphate/ja|P<sub>i</sub>]]の[[Condensation reaction/ja|縮合反応]]と[[succinyl-CoA/ja|スクシニル-CoA]]の[[hydrolysis/ja|加水分解]]は平衡方程式に必要なH<sub>2</sub>Oを含む。
|-
|7
|[[Redox/ja|酸化]]
|[[Succinate/ja]] + [[ubiquinone/ja]] (Q)
|[[Succinate dehydrogenase/ja]]
|[[Fumaric acid/ja|フマル酸塩]] + [[ubiquinol/ja]] (QH<sub>2</sub>)
|酵素の[[prosthetic group/ja|補欠基]]として[[Flavin adenine dinucleotide/ja|FAD]]を使用（反応の第一段階におけるFAD→FADH<sub>2</sub>）<br />この2つの電子は後にETCの複合体IIでQH<sub>2</sub>に移動し、そこで1.5ATPに相当する電子が生成される。
|-
|8
|[[Hydration reaction/ja|水分補給]]
|[[Fumarate/ja]] + H<sub>2</sub>O
|[[Fumarase/ja]]
|''L''-[[Malic acid/ja|リンゴ酸塩]]
|C-C二重結合の水和
|-
|9
|[[Redox/ja|酸化]]
|[[Malate/ja|<small>L</small>-リンゴ酸塩]] + NAD<sup>+</sup>
|[[Malate dehydrogenase/ja]]
|[[Oxaloacetate/ja]] + NADH + H<sup>+</sup>
|可逆的（実際には平衡はリンゴ酸に有利）、[[NADH/ja|NADH]]を生成する（2.5ATPに相当）
|-
|10 / 0
|[[Aldol condensation/ja]]
|[[Oxaloacetic acid/ja|オキサロ酢酸]] + [[Acetyl CoA]] + H<sub>2</sub>O
|[[Citrate synthase/ja]]
|[[Citric acid/ja|クエン酸塩]] + [[Coenzyme A/ja|CoA-SH]]
|これはステップ0と同じで、サイクルを再開する。この反応は不可逆的で、4Cのオキサロ酢酸を6Cの分子に拡張する。
|}
</div>

2つの[[carbon/ja|炭素]]原子が[[oxidation/ja|酸化]]されて[[carbon dioxide/ja|CO<sub>2</sub>]]になり、これらの反応から得られるエネルギーは[[Guanosine triphosphate/ja|GTP]]（またはATP）を介して、また[[NADH/ja|NADH]]と[[Ubiquinol/ja|QH<sub>2</sub>]]の電子として他の代謝プロセスに伝達される。クエン酸サイクルで生成されたNADHは、後に[[oxidative phosphorylation/ja|酸化的リン酸化]]と呼ばれるプロセスの一種で、[[ATP synthase/ja|ATP合成]]を駆動するために酸化される（電子を供与する）ことがある。[[Flavin adenine dinucleotide/ja|FADH<sub>2</sub>]]は[[succinate dehydrogenase/ja|コハク酸デヒドロゲナーゼ]]に共有結合しており、クエン酸サイクルと酸化的リン酸化におけるミトコンドリアの[[electron transport chain/ja|電子輸送鎖]]の両方で機能する酵素である。したがって、FADH<sub>2</sub>は、コハク酸：ユビキノン酸化還元酵素複合体によって触媒される反応の最終電子受容体であり、[[electron transport chain/ja|電子伝達系]]の中間体としても働く[[coenzyme Q/ja|補酵素Q]]への電子伝達を促進する。

ヒトを含む動物のミトコンドリアは、GDPからGTPを生成するタイプと、ADPからATPを生成するタイプの2つの[[succinyl-CoA/ja|スクシニル-CoA]]合成酵素を持っている。植物はATPを産生するタイプ（ADP形成型スクシニル-CoA合成酵素）を持っている。このサイクルに含まれる酵素のいくつかは、[[mitochondrial matrix/ja|ミトコンドリアマトリックス]]内の多酵素[[protein complex/ja|タンパク質複合体]]に緩やかに結合している可能性がある。

GDPを形成するスクシニル-CoA合成酵素によって形成されたGTPは、ATPを形成するために[[nucleoside-diphosphate kinase/ja|ヌクレオシド-二リン酸キナーゼ]]によって利用されるかもしれない（触媒反応はGTP + ADP → GDP + ATP）。

{{clear}}

== 生成物 ==
{{Anchor|Products}}
サイクルの最初のターンの生成物は、1つの[[GTP cyclohydrolase I/ja|GTP]]（または[[Adenosine triphosphate/ja|ATP]]）、3つの[[Nicotinamide adenine dinucleotide/ja|NADH]]、1つの[[Flavin adenine dinucleotide/ja|FADH<sub>2</sub>]]、および2つの[[carbon dioxide/ja|CO<sub>2</sub>]]である。

<div lang="en" dir="ltr" class="mw-content-ltr">
Because two acetyl-CoA [[molecules]] are produced from each [[glucose]] molecule, two cycles are required per glucose molecule. Therefore, at the end of two cycles, the products are: two GTP, six NADH, two [[Flavin adenine dinucleotide|FADH<sub>2</sub>]], and four [[Carbon dioxide|CO<sub>2</sub>]].
</div>

{| class="wikitable"
! width="50%" | 説明 !! 反応物質 !! 生成物
 |-
 | クエン酸サイクルの全反応の合計は次のようになる： || アセチルCoA + 3 NAD<sup>+</sup> + FAD + GDP + P<sub>i</sub> + 2 H<sub>2</sub>O || → CoA-SH + 3 NADH + FADH<sub>2</sub> + 3 H<sup>+</sup> + GTP + 2 CO<sub>2</sub>
 |-
 | [[pyruvate decarboxylation/ja|ピルビン酸酸化]]で起こる反応とクエン酸サイクルで起こる反応を組み合わせると、次のような全体的なピルビン酸酸化反応が得られる： || ピルビン酸イオン + 4 NAD<sup>+</sup> + FAD + GDP + P<sub>i</sub> + 2 H<sub>2</sub>O || → 4 NADH + FADH<sub>2</sub> + 4 H<sup>+</sup> + GTP + 3 CO<sub>2</sub>
 |-
 | 上記の反応と[[glycolysis/ja|解糖]]の過程で起こる反応を組み合わせると、次のような全体的なグルコースの酸化反応（呼吸鎖の反応を除く）が得られる： || グルコース + 10 NAD<sup>+</sup> + 2 FAD + 2 ADP + 2 GDP + 4 P<sub>i</sub> + 2 H<sub>2</sub>O || → 10 NADH + 2 FADH<sub>2</sub> + 10 H<sup>+</sup> + 2 ATP + 2 GTP + 6 CO<sub>2</sub>
|}

P<sub>i</sub>がH<sub>2</sub>PO<sub>4</sub><sup>-</sup>イオンを表し、ADPとGDPがそれぞれADP<sup>2-</sup>イオンとGDP<sup>2-</sup>イオンを表し、ATPとGTPがそれぞれATP<sup>3-</sup>イオンとGTP<sup>3-</sup>イオンを表す場合、上記の反応は釣り合っている。

解糖、クエン酸サイクル、[[oxidative phosphorylation/ja|酸化的リン酸化]]で1個のグルコースを完全に酸化した後に得られるATP分子の総数は、30～38個と推定される。

== 効率 ==
{{Anchor|Efficiency}}
解糖、クエン酸サイクル、[[oxidative phosphorylation/ja|酸化的リン酸化]]におけるグルコース1分子の酸化による[[ATP synthase/ja|ATP]]の理論上の最大収量は38である（1当量のNADHあたり3[[:en:molar equivalent|モル当量]]のATP、1FADH<sub>2</sub>あたり2ATPと仮定）。真核生物では、[[cytoplasm/ja|細胞質]]で行われる[[glycolysis/ja|解糖]]で2当量のNADHと2当量のATPが生成される。もし[[malate-aspartate shuttle/ja|リンゴ酸-アスパラギン酸シャトル]]ではなく[[glycerol phosphate shuttle/ja|グリセロールリン酸シャトル]]を用いて輸送された場合、これら2当量のNADHのミトコンドリアへの輸送は実質的に2当量のATPを消費するため、ATPの正味生産量は36に減少する。さらに、[[Mitochondrion/ja|ミトコンドリア膜]]を横切るプロトンの漏出や[[ATP synthase/ja|ATP合成酵素]]/プロトンポンプのスリップによる[[Mitochondrion/ja|酸化的リン酸化]]の非効率は、NADHと[[Flavin adenine dinucleotide/ja|FADH<sub>2</sub>]]からのATP収量を理論上の最大収量よりも少なくするのが一般的である。従って、観察された収率は、NADHあたり〜2.5ATP、FADH<sub>2</sub>あたり〜1.5ATPに近く、ATPの総純生産量はさらに約30に減少した。新たに修正されたプロトン対ATP比による総ATP収量の評価から、グルコース1分子あたり29.85ATPと推定される。

== バリエーション ==
{{Anchor|Variation}}
クエン酸サイクルは一般的に高度に保存されているが、異なる分類群に見られる酵素には大きな変異がある（このページの図は哺乳類経路の変異型に特有のものであることに注意）。

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Some differences exist between eukaryotes and prokaryotes. The conversion of D-''threo''-isocitrate to 2-oxoglutarate is catalyzed in eukaryotes by the NAD<sup>+</sup>-dependent [http://www.enzyme-database.org/query.php?ec=1.1.1.41 EC 1.1.1.41], while prokaryotes employ the NADP<sup>+</sup>-dependent [http://www.enzyme-database.org/query.php?ec=1.1.1.42 EC 1.1.1.42]. Similarly, the conversion of (''S'')-malate to oxaloacetate is catalyzed in eukaryotes by the NAD<sup>+</sup>-dependent [http://www.enzyme-database.org/query.php?ec=1.1.1.37 EC 1.1.1.37], while most prokaryotes utilize a quinone-dependent enzyme, [http://www.enzyme-database.org/query.php?ec=1.1.5.4 EC 1.1.5.4].
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A step with significant variability is the conversion of succinyl-CoA to succinate. Most organisms utilize [http://www.enzyme-database.org/query.php?ec=6.2.1.5 EC 6.2.1.5], succinate–CoA ligase (ADP-forming) (despite its name, the enzyme operates in the pathway in the direction of ATP formation). In mammals a GTP-forming enzyme, succinate–CoA ligase (GDP-forming) ([http://www.enzyme-database.org/query.php?ec=6.2.1.4 EC 6.2.1.4]) also operates. The level of utilization of each isoform is tissue dependent. In some acetate-producing bacteria, such as ''Acetobacter aceti'', an entirely different enzyme catalyzes this conversion&nbsp;– [http://www.enzyme-database.org/query.php?ec=2.8.3.18 EC 2.8.3.18], succinyl-CoA:acetate CoA-transferase. This specialized enzyme links the TCA cycle with acetate metabolism in these organisms. Some bacteria, such as ''Helicobacter pylori'', employ yet another enzyme for this conversion&nbsp;– succinyl-CoA:acetoacetate CoA-transferase ([http://www.enzyme-database.org/query.php?ec=2.8.3.5 EC 2.8.3.5]).
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Some variability also exists at the previous step&nbsp;– the conversion of 2-oxoglutarate to succinyl-CoA. While most organisms utilize the ubiquitous NAD<sup>+</sup>-dependent 2-oxoglutarate dehydrogenase, some bacteria utilize a ferredoxin-dependent 2-oxoglutarate [[synthase]] ([http://www.enzyme-database.org/query.php?ec=1.2.7.3 EC 1.2.7.3]).
Other organisms, including obligately autotrophic and methanotrophic bacteria and archaea, bypass succinyl-CoA entirely, and convert 2-oxoglutarate to succinate via succinate semialdehyde, using [http://www.enzyme-database.org/query.php?ec=4.1.1.71 EC 4.1.1.71], 2-oxoglutarate decarboxylase, and [http://www.enzyme-database.org/query.php?ec=1.2.1.79 EC 1.2.1.79], succinate-semialdehyde dehydrogenase.
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In [[cancer]], there are substantial [[Warburg effect (oncology)|metabolic derangements]] that occur to ensure the proliferation of tumor cells, and consequently metabolites can accumulate which serve to facilitate [[tumorigenesis]], dubbed onco[[metabolites]]. Among the best characterized oncometabolites is [[2-hydroxyglutarate]] which is produced through a [[heterozygous]] [[gain-of-function mutation]] (specifically a [[Neomorphic mutation|neomorphic]] one) in [[isocitrate dehydrogenase]] (IDH) (which under normal circumstances catalyzes the [[oxidation]] of [[isocitrate]] to [[oxalosuccinate]], which then spontaneously [[Decarboxylation|decarboxylates]] to [[Alpha ketoglutarate|alpha-ketoglutarate]], as discussed above; in this case an additional [[Organic redox reaction|reduction]] step occurs after the formation of alpha-ketoglutarate via [[NADPH]] to yield 2-hydroxyglutarate), and hence IDH is considered an [[oncogene]]. Under physiological conditions, 2-hydroxyglutarate is a minor product of several metabolic pathways as an error but readily converted to alpha-ketoglutarate via hydroxyglutarate dehydrogenase enzymes ([[L2HGDH]] and [[D2HGDH]]) but does not have a known physiologic role in mammalian cells; of note, in cancer, 2-hydroxyglutarate is likely a terminal metabolite as isotope labelling experiments of colorectal cancer cell lines show that its conversion back to alpha-ketoglutarate is too low to measure. In cancer, 2-hydroxyglutarate serves as a [[Competitive inhibition|competitive inhibitor]] for a number of enzymes that facilitate reactions via alpha-ketoglutarate in alpha-ketoglutarate-dependent [[dioxygenase]]s. This mutation results in several important changes to the metabolism of the cell. For one thing, because there is an extra NADPH-catalyzed reduction, this can contribute to depletion of cellular stores of NADPH and also reduce levels of alpha-ketoglutarate available to the cell. In particular, the depletion of NADPH is problematic because NADPH is highly compartmentalized and cannot freely diffuse between the organelles in the cell. It is produced largely via the [[pentose phosphate pathway]] in the cytoplasm. The depletion of NADPH results in increased [[oxidative stress]] within the cell as it is a required cofactor in the production of [[Glutathione|GSH]], and this oxidative stress can result in DNA damage. There are also changes on the genetic and epigenetic level through the function of [[Histone code|histone lysine demethylases]] (KDMs) and [[Ten-Eleven Translocation 2|ten-eleven translocation]] (TET) enzymes; ordinarily TETs hydroxylate [[5-Methylcytosine|5-methylcytosines]] to prime them for demethylation. However, in the absence of alpha-ketoglutarate this cannot be done and there is hence hypermethylation of the cell's DNA, serving to promote [[Epithelial–mesenchymal transition|epithelial-mesenchymal transition (EMT)]] and inhibit cellular differentiation. A similar phenomenon is observed for the Jumonji C family of KDMs which require a hydroxylation to perform demethylation at the epsilon-amino methyl group.Additionally, the inability of prolyl hydroxylases to catalyze reactions results in stabilization of [[HIF1A|hypoxia-inducible factor alpha]], which is necessary to promote degradation of the latter (as under conditions of low oxygen there will not be adequate substrate for hydroxylation). This results in a [[Pseudohypoxia|pseudohypoxic]] phenotype in the cancer cell that promotes [[angiogenesis]], metabolic reprogramming, [[cell growth]], and [[Cell migration|migration]].
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== Regulation ==
'''Allosteric regulation by metabolites'''. The regulation of the citric acid cycle is largely determined by product inhibition and substrate availability. If the cycle were permitted to run unchecked, large amounts of [[Metabolism|metabolic]] energy could be wasted in overproduction of reduced coenzyme such as NADH and ATP. The major eventual substrate of the cycle is ADP which gets converted to ATP. A reduced amount of ADP causes accumulation of precursor NADH which in turn can inhibit a number of enzymes. NADH, a product of all dehydrogenases in the citric acid cycle with the exception of [[succinate dehydrogenase]], inhibits [[pyruvate dehydrogenase]], [[isocitrate dehydrogenase]], [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]], and also [[citrate synthase]]. [[Acetyl-coA]] inhibits [[pyruvate dehydrogenase]], while [[succinyl-CoA]] inhibits alpha-ketoglutarate dehydrogenase and [[citrate synthase]]. When tested in vitro with TCA enzymes, '''ATP''' inhibits [[citrate synthase]] and [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]]; however, ATP levels do not change more than 10% in vivo between rest and vigorous exercise. There is no known [[allosteric]] mechanism that can account for large changes in reaction rate from an allosteric effector whose concentration changes less than 10%.
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'''Citrate''' is used for feedback inhibition, as it inhibits [[phosphofructokinase]], an enzyme involved in [[glycolysis]] that catalyses formation of [[fructose 1,6-bisphosphate]], a precursor of pyruvate. This prevents a constant high rate of flux when there is an accumulation of citrate and a decrease in substrate for the enzyme.
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'''Regulation by calcium'''. Calcium is also used as a regulator in the citric acid cycle. Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation. It activates [[pyruvate dehydrogenase phosphatase]] which in turn activates the [[pyruvate dehydrogenase complex]]. Calcium also activates [[isocitrate dehydrogenase]] and [[Alpha-ketoglutarate dehydrogenase|α-ketoglutarate dehydrogenase]]. This increases the reaction rate of many of the steps in the cycle, and therefore increases flux throughout the pathway.
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'''Transcriptional regulation'''. Recent work has demonstrated an important link between intermediates of the citric acid cycle and the regulation of [[hypoxia-inducible factors]] ([[HIF1A|HIF]]). HIF plays a role in the regulation of oxygen [[homeostasis]], and is a transcription factor that targets [[angiogenesis]], [[Vascular remodelling in the embryo|vascular remodeling]], [[glucose]] utilization, iron transport and [[apoptosis]]. HIF is synthesized constitutively, and [[hydroxylation]] of at least one of two critical [[proline]] residues mediates their interaction with the von Hippel Lindau [[E3 ubiquitin ligase]] complex, which targets them for rapid degradation. This reaction is catalysed by [[prolyl hydroxylase|prolyl 4-hydroxylases]]. Fumarate and succinate have been identified as potent inhibitors of prolyl hydroxylases, thus leading to the stabilisation of HIF.
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== Major metabolic pathways converging on the citric acid cycle ==
Several [[catabolic]] pathways converge on the citric acid cycle. Most of these reactions add intermediates to the citric acid cycle, and are therefore known as [[anaplerotic reactions]], from the Greek meaning to "fill up". These increase the amount of acetyl CoA that the cycle is able to carry, increasing the [[Mitochondrion|mitochondrion's]] capability to carry out respiration if this is otherwise a limiting factor. Processes that remove intermediates from the cycle are termed "cataplerotic" reactions.
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In this section and in the next, the citric acid cycle intermediates are indicated in ''italics'' to distinguish them from other substrates and end-products.
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[[Pyruvate]] molecules produced by [[glycolysis]] are [[active transport|actively transported]] across the inner [[Mitochondrion|mitochondrial]] membrane, and into the matrix. Here they can be [[Redox|oxidized]] and combined with [[coenzyme A]] to form CO<sub>2</sub>, ''[[acetyl-CoA]]'', and [[NADH]], as in the normal cycle.
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However, it is also possible for pyruvate to be [[carboxylated]] by [[pyruvate carboxylase]] to form ''oxaloacetate''. This latter reaction "fills up" the amount of ''oxaloacetate'' in the citric acid cycle, and is therefore an anaplerotic reaction, increasing the cycle's capacity to metabolize ''acetyl-CoA'' when the tissue's energy needs (e.g. in [[striated muscle tissue|muscle]]) are suddenly increased by activity.
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In the citric acid cycle all the intermediates (e.g. ''[[Citric acid|citrate]]'', ''iso-citrate'', ''[[Alpha-Ketoglutaric acid|alpha-ketoglutarate]]'', ''[[Succinic acid|succinate]]'', ''[[Fumaric acid|fumarate]]'', ''[[Malic acid|malate]]'', and ''[[Oxaloacetic acid|oxaloacetate]]'') are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of any one of them to the cycle has an anaplerotic effect, and its removal has a cataplerotic effect. These anaplerotic and cataplerotic reactions will, during the course of the cycle, increase or decrease the amount of ''oxaloacetate'' available to combine with ''acetyl-CoA'' to form ''citric acid''. This in turn increases or decreases the rate of [[Adenosine triphosphate|ATP]] production by the mitochondrion, and thus the availability of ATP to the cell.
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''[[Acetyl-CoA]]'', on the other hand, derived from pyruvate oxidation, or from the [[beta-oxidation]] of [[fatty acids]], is the only fuel to enter the citric acid cycle. With each turn of the cycle one molecule of ''acetyl-CoA'' is consumed for every molecule of ''oxaloacetate'' present in the mitochondrial matrix, and is never regenerated. It is the oxidation of the acetate portion of ''acetyl-CoA'' that produces CO<sub>2</sub> and water, with the energy thus released captured in the form of ATP. The three steps of beta-oxidation resemble the steps that occur in the production of oxaloacetate from succinate in the TCA cycle. Acyl-CoA is oxidized to trans-Enoyl-CoA while FAD is reduced to FADH<sub>2</sub>, which is similar to the oxidation of succinate to fumarate. Following, [[Trans-2-enoyl-CoA reductase (NADPH)|trans-Enoyl-CoA]] is hydrated across the double bond to beta-hydroxyacyl-CoA, just like fumarate is hydrated to malate. Lastly, beta-hydroxyacyl-CoA is oxidized to beta-ketoacyl-CoA while NAD+ is reduced to NADH, which follows the same process as the oxidation of malate to [[Oxaloacetic acid|oxaloacetate]].
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In the liver, the carboxylation of [[cytosol]]ic pyruvate into intra-mitochondrial ''oxaloacetate'' is an early step in the [[gluconeogenesis|gluconeogenic]] pathway which converts [[lactic acid|lactate]] and de-aminated [[alanine]] into glucose, under the influence of high levels of [[glucagon]] and/or [[epinephrine]] in the blood. Here the addition of ''oxaloacetate'' to the mitochondrion does not have a net anaplerotic effect, as another citric acid cycle intermediate (''malate'') is immediately removed from the mitochondrion to be converted into cytosolic oxaloacetate, which is ultimately converted into glucose, in a process that is almost the reverse of [[glycolysis]].
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In [[protein catabolism]], [[protein]]s are broken down by [[protease]]s into their constituent amino acids. Their carbon skeletons (i.e. the de-aminated amino acids) may either enter the citric acid cycle as intermediates (e.g. ''alpha-ketoglutarate'' derived from glutamate or glutamine), having an anaplerotic effect on the cycle, or, in the case of [[leucine]], [[isoleucine]], [[lysine]], [[phenylalanine]], [[tryptophan]], and [[tyrosine]], they are converted into ''acetyl-CoA'' which can be burned to CO<sub>2</sub> and water, or used to form [[ketone bodies]], which too can only be burned in tissues other than the liver where they are formed, or excreted via the urine or breath. These latter amino acids are therefore termed "ketogenic" amino acids, whereas those that enter the citric acid cycle as intermediates can only be cataplerotically removed by entering the gluconeogenic pathway via ''malate'' which is transported out of the mitochondrion to be converted into cytosolic oxaloacetate and ultimately into [[glucose]]. These are the so-called "glucogenic" amino acids. De-aminated alanine, cysteine, glycine, serine, and threonine are converted to pyruvate and can consequently either enter the citric acid cycle as ''oxaloacetate'' (an anaplerotic reaction) or as ''acetyl-CoA'' to be disposed of as CO<sub>2</sub> and water.
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In [[fat catabolism]], [[triglyceride]]s are [[hydrolysis|hydrolyzed]] to break them into [[fatty acid]]s and [[glycerol]]. In the liver the glycerol can be converted into glucose via [[dihydroxyacetone phosphate]] and [[glyceraldehyde-3-phosphate]] by way of [[gluconeogenesis]]. In skeletal muscle, glycerol is used in [[glycolysis]] by converting glycerol into [[Glycerol 3-phosphate|glycerol-3-phosphate]], then into [[Dihydroxyacetone phosphate|dihydroxyacetone phosphate (DHAP)]], then into glyceraldehyde-3-phosphate.
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In many tissues, especially heart and skeletal [[muscle tissue]], [[fatty acid]]s are broken down through a process known as [[beta oxidation]], which results in the production of mitochondrial ''acetyl-CoA'', which can be used in the citric acid cycle. [[Beta oxidation]] of [[fatty acid]]s with an odd number of [[methylene bridge]]s produces [[propionyl-CoA]], which is then converted into ''[[succinyl-CoA]]'' and fed into the citric acid cycle as an anaplerotic intermediate.
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The total energy gained from the complete breakdown of one (six-carbon) molecule of glucose by [[glycolysis]], the formation of 2 ''acetyl-CoA'' molecules, their catabolism in the citric acid cycle, and oxidative phosphorylation equals about 30 [[Adenosine triphosphate|ATP molecules]], in [[eukaryote]]s. The number of ATP molecules derived from the beta oxidation of a 6 carbon segment of a fatty acid chain, and the subsequent [[Redox|oxidation]] of the resulting 3 molecules of [[Acetyl-CoA carboxylase|''acetyl-CoA'' is]] 40.
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== Citric acid cycle intermediates serve as substrates for biosynthetic processes ==
In this subheading, as in the previous one, the TCA intermediates are identified by ''italics''.
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Several of the citric acid cycle intermediates are used for the synthesis of important compounds, which will have significant cataplerotic effects on the cycle.
''Acetyl-CoA'' cannot be transported out of the mitochondrion. To obtain cytosolic acetyl-CoA, ''citrate'' is removed from the citric acid cycle and carried across the inner mitochondrial membrane into the cytosol. There it is cleaved by [[ATP citrate lyase]] into acetyl-CoA and oxaloacetate. The oxaloacetate is returned to mitochondrion as ''malate'' (and then converted back into ''oxaloacetate'' to transfer more ''acetyl-CoA'' out of the mitochondrion). The cytosolic acetyl-CoA is used for [[fatty acid synthesis]] and the [[Mevalonate pathway|production of cholesterol]]. [[Cholesterol]] can, in turn, be used to synthesize the [[Steroid#Steroidogenesis|steroid hormones]], [[Bile acids|bile salts]], and [[vitamin D]].
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The carbon skeletons of many [[Essential amino acid|non-essential amino acids]] are made from citric acid cycle intermediates. To turn them into amino acids the [[Keto acid|alpha keto-acids]] formed from the citric acid cycle intermediates have to acquire their amino groups from [[glutamate]] in a [[transamination]] reaction, in which [[Pyridoxine|pyridoxal phosphate]] is a cofactor. In this reaction the glutamate is converted into [[alpha-Ketoglutaric acid|''alpha-ketoglutarate'']], which is a citric acid cycle intermediate. The intermediates that can provide the [[Skeletal formula|carbon skeletons]] for amino acid synthesis are ''[[Oxaloacetic acid|oxaloacetate]]'' which forms [[aspartate]] and [[asparagine]]; and ''alpha-ketoglutarate'' which forms [[glutamine]], [[proline]], and [[arginine]].
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Of these amino acids, aspartate and glutamine are used, together with carbon and nitrogen atoms from other sources, to form the [[purines]] that are used as the bases in [[DNA]] and [[RNA]], as well as in [[Adenosine triphosphate|ATP]], [[Adenosine monophosphate|AMP]], [[Guanosine triphosphate|GTP]], [[Nicotinamide adenine dinucleotide|NAD]], [[Flavin adenine dinucleotide|FAD]] and [[Coenzyme A|CoA]].
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The [[pyrimidines]] are partly assembled from aspartate (derived from ''oxaloacetate''). The pyrimidines, [[thymine]], [[cytosine]] and [[uracil]], form the complementary bases to the purine bases in DNA and RNA, and are also components of [[Cytidine triphosphate|CTP]], [[Uridine monophosphate|UMP]], [[Uridine diphosphate|UDP]] and [[Uridine triphosphate|UTP]].
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The majority of the carbon atoms in the [[porphyrin]]s come from the citric acid cycle intermediate, ''[[succinyl-CoA]]''. These molecules are an important component of the [[hemoprotein]]s, such as [[hemoglobin]], [[myoglobin]] and various [[cytochrome]]s.
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During gluconeogenesis [[Gluconeogenesis#Pathway|mitochondrial ''oxaloacetate'' is reduced to ''malate'']] which is then transported out of the mitochondrion, to be oxidized back to oxaloacetate in the cytosol. Cytosolic oxaloacetate is then [[Decarboxylation|decarboxylated]] to [[phosphoenolpyruvate]] by [[phosphoenolpyruvate carboxykinase]], which is the rate limiting step in the conversion of nearly all the [[Glucogenic amino acid|gluconeogenic]] precursors (such as the glucogenic amino acids and lactate) into glucose by the [[liver]] and [[kidney]].
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Because the citric acid cycle is involved in both [[catabolic]] and [[anabolic]] processes, it is known as an [[amphibolic]] pathway.
Evan M.W.Duo
{{TCACycle WP78}}
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== 循環乳酸を介してTCAサイクルに供給されるグルコース ==
{{Anchor|Glucose feeds the TCA cycle via circulating lactate}}
[[Lactic acid/ja|乳酸]]の[[Metabolic pathway/ja|代謝]]的役割は、[[Tissue (biology)/ja|組織]]、[[DPH Cytopathy/ja|DPH細胞症]]などの[[mitochondrial disease/ja|ミトコンドリア細胞症]]、および[[oncology/ja|腫瘍学]]の科学分野（[[Neoplasm/ja|腫瘍]]）の燃料としてよく認識されている。古典的な[[cori cycle/ja|コリサイクル]]では、筋肉が乳酸を産生し、それが[[liver/ja|肝臓]]で[[gluconeogenesis/ja|糖新生]]のために取り込まれる。新しい研究では、乳酸はTCAサイクルの[[carbon/ja|炭素]]源として使用できることが示唆されている。

== 進化 ==
{{Anchor|Evolution}}
クエン酸サイクルの構成要素は[[anaerobic bacteria/ja|嫌気性細菌]]に由来すると考えられており、TCAサイクル自体も複数回進化した可能性がある。基質は[[persulfate/ja|過硫酸塩]]ラジカルの存在下でほとんどの反応を自発的に行っているようである。 理論的には、TCAサイクルに代わるものがいくつか存在するが、TCAサイクルが最も効率的であるように思われる。いくつかのTCAサイクルに代わるものが独立して進化してきたとすれば、それらはすべてTCAサイクルに[[convergent evolution/ja|収斂]]したように見える。

== こちらも参照 ==
* [[Calvin cycle/ja]]
* [[Glyoxylate cycle/ja]]
* [[Reverse Krebs cycle/ja|逆（還元）クレブスサイクル]]
* [[w:simple:Krebs cycle|Krebs cycle (simple English)]]

== 外部リンク ==
* [https://www.science.smith.edu/departments/Biology/Bio231/krebs.html An animation of the citric acid cycle] at [[Smith College]]
* [https://biocyc.org/META/NEW-IMAGE?object=TCA-VARIANTS Citric acid cycle variants] at [[Wikipedia:MetaCyc|MetaCyc]]
* [https://www.genome.ad.jp/kegg/pathway/map/map00020.html Pathways connected to the citric acid cycle] {{Webarchive|url=https://web.archive.org/web/20081026150930/http://www.genome.ad.jp/kegg/pathway/map/map00020.html |date=2008-10-26 }} at [[KEGG/ja|Kyoto Encyclopedia of Genes and Genomes]]
* [http://www.metpath.teithe.gr/?part=TCA&lang=en ''metpath'': Interactive representation of the citric acid cycle]

{{Cellular respiration/ja}}
{{citric acid cycle/ja}}
{{MetabolismMap}}
{{Citric acid cycle enzymes/ja}}

{{DEFAULTSORT:Citric Acid Cycle}}
[[Category:Citric acid cycle| ]]
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[[Category:Cellular respiration]]
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