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Pathway Description

Cardiolipin Biosynthesis CL(14:0/18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z))

Homo sapiens

Category:

Metabolite Pathway

Sub-Category:

Metabolic

Created: 2024-02-05

Last Updated: 2024-11-12

Cardiolipin (CL) is an important component of the inner mitochondrial membrane where it constitutes about 20% of the total lipid composition. It is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism (Wikipedia). Cardiolipin biosynthesis occurs mainly in the mitochondria, but there also exists an alternative synthesis route for CDP-diacylglycerol that takes place in the endoplasmic reticulum. This second route may supplement this pathway. All membrane-localized enzymes are coloured dark green in the image. First, dihydroxyacetone phosphate (or glycerone phosphate) from glycolysis is used by the cytosolic enzyme glycerol-3-phosphate dehydrogenase [NAD(+)] to synthesize sn-glycerol 3-phosphate. Second, the mitochondrial outer membrane enzyme glycerol-3-phosphate acyltransferase esterifies an acyl-group to the sn-1 position of sn-glycerol 3-phosphate to form 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid or LPA). Third, the enzyme 1-acyl-sn-glycerol-3-phosphate acyltransferase converts LPA into phosphatidic acid (PA or 1,2-diacyl-sn-glycerol 3-phosphate) by esterifying an acyl-group to the sn-2 position of the glycerol backbone. PA is then transferred to the inner mitochondrial membrane to continue cardiolipin synthesis. Fourth, magnesium-dependent phosphatidate cytidylyltransferase catalyzes the conversion of PA into CDP-diacylglycerol. Fifth, CDP-diacylglycerol--glycerol-3-phosphate 3-phosphatidyltransferase synthesizes phosphatidylglycerophosphate (PGP). Sixth, phosphatidylglycerophosphatase and protein-tyrosine phosphatase dephosphorylates PGP to form phosphatidylglycerol (PG). Last, cardiolipin synthase catalyzes the synthesis of cardiolipin by transferring a phosphatidyl group from a second CDP-diacylglycerol to PG. It requires a divalent metal cation cofactor.

References

Cardiolipin Biosynthesis CL(14:0/18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)/18:1(9Z)) References

Houtkooper RH, Akbari H, van Lenthe H, Kulik W, Wanders RJ, Frentzen M, Vaz FM: Identification and characterization of human cardiolipin synthase. FEBS Lett. 2006 May 29;580(13):3059-64. doi: 10.1016/j.febslet.2006.04.054. Epub 2006 Apr 27.

Pubmed: 16678169

Prasad SS, Garg A, Agarwal AK: Enzymatic activities of the human AGPAT isoform 3 and isoform 5: localization of AGPAT5 to mitochondria. J Lipid Res. 2011 Mar;52(3):451-62. doi: 10.1194/jlr.M007575. Epub 2010 Dec 20.

Pubmed: 21173190

Tian HF, Feng JM, Wen JF: The evolution of cardiolipin biosynthesis and maturation pathways and its implications for the evolution of eukaryotes. BMC Evol Biol. 2012 Mar 13;12:32. doi: 10.1186/1471-2148-12-32.

Pubmed: 22409430

Chen YQ, Kuo MS, Li S, Bui HH, Peake DA, Sanders PE, Thibodeaux SJ, Chu S, Qian YW, Zhao Y, Bredt DS, Moller DE, Konrad RJ, Beigneux AP, Young SG, Cao G: AGPAT6 is a novel microsomal glycerol-3-phosphate acyltransferase. J Biol Chem. 2008 Apr 11;283(15):10048-57. doi: 10.1074/jbc.M708151200. Epub 2008 Jan 31.

Pubmed: 18238778

Ou X, Ji C, Han X, Zhao X, Li X, Mao Y, Wong LL, Bartlam M, Rao Z: Crystal structures of human glycerol 3-phosphate dehydrogenase 1 (GPD1). J Mol Biol. 2006 Mar 31;357(3):858-69. doi: 10.1016/j.jmb.2005.12.074. Epub 2006 Jan 18.

Pubmed: 16460752

Joshi M, Eagan J, Desai NK, Newton SA, Towne MC, Marinakis NS, Esteves KM, De Ferranti S, Bennett MJ, McIntyre A, Beggs AH, Berry GT, Agrawal PB: A compound heterozygous mutation in GPD1 causes hepatomegaly, steatohepatitis, and hypertriglyceridemia. Eur J Hum Genet. 2014 Oct;22(10):1229-32. doi: 10.1038/ejhg.2014.8. Epub 2014 Feb 19.

Pubmed: 24549054

Menaya J, Gonzalez-Manchon C, Parrilla R, Ayuso MS: Molecular cloning, sequencing and expression of a cDNA encoding a human liver NAD-dependent alpha-glycerol-3-phosphate dehydrogenase. Biochim Biophys Acta. 1995 May 17;1262(1):91-4. doi: 10.1016/0167-4781(95)00069-s.

Pubmed: 7772607

Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.

Pubmed: 14702039

Highlighted elements will appear in red.

Highlight Compounds

	Hydrogen Ion
	NADH

Highlight Proteins

Glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic

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