Carnitine palmitoyltransferase I

Last updated
CPT1A
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CPT1A , carnitine palmitoyltransferase 1A (liver), CPT1, CPT1-L, L-CPT1, carnitine palmitoyltransferase 1A
External IDs OMIM: 600528; MGI: 1098296; HomoloGene: 1413; GeneCards: CPT1A; OMA:CPT1A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1374

12894

Ensembl

ENSG00000110090

ENSMUSG00000024900

UniProt

P50416

P97742

RefSeq (mRNA)

NM_001031847
NM_001876

NM_013495

RefSeq (protein)

NP_001027017
NP_001867

NP_038523

Location (UCSC) Chr 11: 68.75 – 68.84 Mb Chr 19: 3.37 – 3.44 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often palmitoylcarnitine (thus the name), but other fatty acids may also be substrates. [5] [6] It is part of a family of enzymes called carnitine acyltransferases. [7] This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.

Contents

Three isoforms of CPT1 are currently known: CPT1A, CPT1B, and CPT1C. CPT1 is associated with the outer mitochondrial membrane. This enzyme can be inhibited by malonyl CoA, the first committed intermediate produced during fatty acid synthesis. Its role in fatty acid metabolism makes CPT1 important in many metabolic disorders such as diabetes. Since its crystal structure is not known, its exact mechanism of action remains to be determined.

Structure

Carnitine bound in the catalytic site of CRAT, an enzyme homologous to CPT1. The catalytic histidine and stabilizing serine residues are colored orange. Carnitine Acetyltransferase and Carnitine.png
Carnitine bound in the catalytic site of CRAT, an enzyme homologous to CPT1. The catalytic histidine and stabilizing serine residues are colored orange.

CPT1 is an integral membrane protein that exists in three isoforms in mammalian tissues: CPT1A, CPT1B and CPT1C. The first two are expressed on the outer mitochondrial membrane of most tissues, but their relative proportions varies between tissues. CPT1A predominates in lipogenic tissues like liver, whereas CPT1B predominates in tissues like heart and skeletal muscle that have a high fatty acid oxidative capacity brown adipose cells. [8] [9] Both isoforms are integral proteins of the mitochondrial outer membrane through two transmembrane regions in the peptide chain. The membrane topology of CPT1A was described by Fraser et al. in 1997. [10] It is polytopic, with both the N- and C-termini exposed on the cytosolic aspect of the OMM, with a short loop linking the two transmembrane domains protruding into the mitochondrial inter-membrane space.

The third isoform (CPT1C), was identified in 2002 and is expressed in both mitochondria and the endoplasmic reticulum. [11] It is normally expressed only in neurones (brain), although its expression is altered in certain cancer cell types. [12] [13]

The exact structure of any of the CPT1 isoforms has not yet been determined, although a variety of in silico models for CPT1 have been created based on closely related carnitine acyltransferases, such as carnitine acetyltransferase (CRAT). [14]

An important structural difference between CPT1 and CPT2, CRAT and carnitine octanoyltransferase (COT) is that CPT1 contains an additional domain at its N-terminal consisting of about 160 amino acids. It has been determined that this additional N-terminal domain is important for the key inhibitory molecule of CPT1, malonyl-CoA, and acts like a switch that makes CPT1A more or less sensitive to malonyl-CoA inhibition. [15]

Two distinct binding sites have been proposed to exist in CPT1A and CPT1B. The "A site" or "CoA site" appears to bind both malonyl-CoA and palmitoyl-CoA, as well as other molecules containing coenzyme A, suggesting that the enzyme binds these molecules via interaction with the coenzyme A moiety. It has been suggested that malonyl-CoA may behave as a competitive inhibitor of CPT1A at this site. A second "O site" has been proposed to bind malonyl-CoA more tightly than the A site. Unlike the A site, the O site binds to malonyl-CoA via the dicarbonyl group of the malonate moiety of malonyl-CoA. The binding of malonyl-CoA to either the A and O sites inhibits the action of CPT1A by excluding the binding of carnitine to CPT1A. [16] Since a crystal structure of CPT1A has yet to be isolated and imaged, its exact structure remains to be elucidated.

Function

Enzyme mechanism

Because crystal structure data is currently unavailable, the exact mechanism of CPT1 is not currently known. A couple different possible mechanisms for CPT1 have been postulated, both of which include the histidine residue 473 as the key catalytic residue. One such mechanism based upon a carnitine acetyltransferase model is shown below in which the His 473 deprotonates carnitine while a nearby serine residue stabilizes the tetrahedral oxyanion intermediate. [7]

A different mechanism has been proposed that suggests that a catalytic triad composed of residues Cys-305, His-473, and Asp-454 carries out the acyl-transferring step of catalysis. [17] This catalytic mechanism involves the formation of a thioacyl-enzyme covalent intermediate with Cys-305.

Carnitine palmitoyltransferase mechanism. Carnitine Palmitoyltransferase I Mechanism.png
Carnitine palmitoyltransferase mechanism.

Biological function

The carnitine palmitoyltransferase system is an essential step in the beta-oxidation of long chain fatty acids. This transfer system is necessary because, while fatty acids are activated (in the form of a thioester linkage to coenzyme A) on the outer mitochondrial membrane, the activated fatty acids must be oxidized within the mitochondrial matrix. Long chain fatty acids such as palmitoyl-CoA, unlike short- and medium-chain fatty acids, cannot freely diffuse through the mitochondrial inner membrane, and require a shuttle system to be transported to the mitochondrial matrix. [18]

Acyl-CoA from cytosol to the mitochondrial matrix Acyl-CoA from cytosol to the mitochondrial matrix.svg
Acyl-CoA from cytosol to the mitochondrial matrix

Carnitine palmitoyltransferase I is the first component and rate-limiting step of the carnitine palmitoyltransferase system, catalyzing the transfer of the acyl group from coenzyme A to carnitine to form palmitoylcarnitine. A translocase then shuttles the acyl carnitine across the inner mitochondrial membrane where it is converted back into palmitoyl-CoA.

By acting as an acyl group acceptor, carnitine may also play the role of regulating the intracellular CoA:acyl-CoA ratio. [19]

Regulation

CPT1 is inhibited by malonyl-CoA, although the exact mechanism of inhibition remains unknown. The CPT1 skeletal muscle and heart isoform, CPT1B, has been shown to be 30-100-fold more sensitive to malonyl-CoA inhibition than CPT1A. This inhibition is a good target for future attempts to regulate CPT1 for the treatment of metabolic disorders. [20]

Acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the formation of malonyl-CoA from acetyl-CoA, is important in the regulation of fatty acid metabolism. Scientists have demonstrated that ACC2 knockout mice have reduced body fat and weight when compared to wild type mice. This is a result of decreased activity of ACC which causes a subsequent decrease in malonyl-CoA concentrations. These decreased malonyl-CoA levels in turn prevent inhibition of CPT1, causing an ultimate increase in fatty acid oxidation. [21] Since heart and skeletal muscle cells have a low capacity for fatty acid synthesis, ACC may act purely as a regulatory enzyme in these cells.

Clinical significance

The "CPT1A" form is associated with carnitine palmitoyltransferase I deficiency. [22] This rare disorder confers risk for hepatic encephalopathy, hypoketotic hypoglycemia, seizures, and sudden unexpected death in infancy. [23]

CPT1 is associated with type 2 diabetes and insulin resistance. Such diseases, along with many other health problems, cause free fatty acid (FFA) levels in humans to become elevated, fat to accumulate in skeletal muscle, and decreases the ability of muscles to oxidize fatty acids. CPT1 has been implicated in contributing to these symptoms. The increased levels of malonyl-CoA caused by hyperglycemia and hyperinsulinemia inhibit CPT1, which causes a subsequent decrease in the transport of long chain fatty acids into muscle and heart mitochondria, decreasing fatty acid oxidation in such cells. The shunting of LCFAs away from mitochondria leads to the observed increase in FFA levels and the accumulation of fat in skeletal muscle. [24] [25]

Its importance in fatty acid metabolism makes CPT1 a potentially useful enzyme to focus on in the development of treatments of many other metabolic disorders as well. [26]

Interactions

CPT1 is known to interact with many proteins, including ones from the NDUF family, PKC1, and ENO1. [27]

In HIV, Vpr enhances PPARbeta/delta-induced PDK4, carnitine palmitoyltransferase I (CPT1) mRNA expression in cells. [28] Knockdown of CPT1A by shRNA library screening inhibits HIV-1 replication in cultured Jurkat T-cells. [29]

See also

Related Research Articles

<span class="mw-page-title-main">Carnitine</span> Amino acid active in mitochondria

Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for free energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians, synthesize enough L-carnitine in vivo.

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters the citric acid cycle, generating NADH and FADH2, which are electron carriers used in the electron transport chain. It is named as such because the beta carbon of the fatty acid chain undergoes oxidation and is converted to a carbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

<span class="mw-page-title-main">Inborn error of lipid metabolism</span> Medical condition

Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.

<span class="mw-page-title-main">Acetyl-CoA carboxylase</span> Enzyme that regulates the metabolism of fatty acids

Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes and in the chloroplasts of most plants and algae, whereas it is a large, multi-domain enzyme in the cytoplasm of most eukaryotes. The most important function of ACC is to provide the malonyl-CoA substrate for the biosynthesis of fatty acids. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. The human genome contains the genes for two different ACCs—ACACA and ACACB.

<span class="mw-page-title-main">Malonyl-CoA</span> Chemical compound

Malonyl-CoA is a coenzyme A derivative of malonic acid.

<span class="mw-page-title-main">Carnitine palmitoyltransferase I deficiency</span> Medical condition

Carnitine palmitoyltransferase I deficiency is a rare metabolic disorder that prevents the body from converting certain fats called long-chain fatty acids(LCFA) into energy, particularly during periods without food. It is caused by a mutation in CPT1A on chromosome 11.

<span class="mw-page-title-main">Carnitine palmitoyltransferase II deficiency</span> Medical condition

Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT-II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source. The disorder presents in one of three clinical forms: lethal neonatal, severe infantile hepatocardiomuscular and myopathic.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Palmitoylcarnitine</span> Chemical compound

Palmitoylcarnitine is an ester derivative of carnitine involved in the metabolism of fatty acids. During the tricarboxylic acid cycle (TCA), fatty acids undergo a process known as β-oxidation to produce energy in the form of ATP. β-oxidation occurs primarily within mitochondria, however the mitochondrial membrane prevents the entry of long chain fatty acids (>C10), so the conversion of fatty acids such as palmitic acid is key. Palmitic acid is brought to the cell and once inside the cytoplasm is first converted to Palmitoyl-CoA. Palmitoyl-CoA has the ability to freely pass the outer mitochondrial membrane, but the inner membrane is impermeable to the Acyl-CoA and thioester forms of various long-chain fatty acids such as palmitic acid. The palmitoyl-CoA is then enzymatically transformed into palmitoylcarnitine via the Carnitine O-palmitoyltransferase family. The palmitoylcarnitine is then actively transferred into the inner membrane of the mitochondria via the carnitine-acylcarnitine translocase. Once inside the inner mitochondrial membrane, the same Carnitine O-palmitoyltransferase family is then responsible for transforming the palmitoylcarnitine back to the palmitoyl-CoA form.

<span class="mw-page-title-main">Carnitine O-palmitoyltransferase</span>

Carnitine O-palmitoyltransferase is a mitochondrial transferase enzyme involved in the metabolism of palmitoylcarnitine into palmitoyl-CoA. A related transferase is carnitine acyltransferase.

<span class="mw-page-title-main">Malonyl-CoA decarboxylase</span> Class of enzymes

Malonyl-CoA decarboxylase, is found in bacteria and humans and has important roles in regulating fatty acid metabolism and food intake, and it is an attractive target for drug discovery. It is an enzyme associated with Malonyl-CoA decarboxylase deficiency. In humans, it is encoded by the MLYCD gene.

<span class="mw-page-title-main">Acyl-CoA</span> Group of coenzymes that metabolize fatty acids

Acyl-CoA is a group of coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the common biochemical energy carrier.

Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of living organisms, including bacteria and animals. It includes three major steps:

Palmitoyl-CoA is an acyl-CoA thioester. It is an "activated" form of palmitic acid and can be transported into the mitochondrial matrix by the carnitine shuttle system, and once inside can participate in beta-oxidation. Alternatively, palmitoyl-CoA is used as a substrate in the biosynthesis of sphingosine.

Pantothenate kinase (EC 2.7.1.33, PanK; CoaA) is the first enzyme in the Coenzyme A (CoA) biosynthetic pathway. It phosphorylates pantothenate (vitamin B5) to form 4'-phosphopantothenate at the expense of a molecule of adenosine triphosphate (ATP). It is the rate-limiting step in the biosynthesis of CoA.

The Randle cycle, also known as the glucose fatty-acid cycle, is a metabolic process involving the competition of glucose and fatty acids for substrates. It is theorized to play a role in explaining type 2 diabetes and insulin resistance.

Palmitoyl-CoA hydrolase (EC 3.1.2.2) is an enzyme in the family of hydrolases that specifically acts on thioester bonds. It catalyzes the hydrolysis of long chain fatty acyl thioesters of acyl carrier protein or coenzyme A to form free fatty acid and the corresponding thiol:

<span class="mw-page-title-main">Carnitine O-octanoyltransferase</span>

Carnitine O-octanoyltransferase is a member of the transferase family, more specifically a carnitine acyltransferase, a type of enzyme which catalyzes the transfer of acyl groups from acyl-CoAs to carnitine, generating CoA and an acyl-carnitine. The systematic name of this enzyme is octanoyl-CoA:L-carnitine O-octanoyltransferase. Other names in common use include medium-chain/long-chain carnitine acyltransferase, carnitine medium-chain acyltransferase, easily solubilized mitochondrial carnitine palmitoyltransferase, and overt mitochondrial carnitine palmitoyltransferase. Specifically, CROT catalyzes the chemical reaction:

Fatty acyl-CoA esters are fatty acid derivatives formed of one fatty acid, a 3'-phospho-AMP linked to phosphorylated pantothenic acid (vitamin B5) and cysteamine.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000110090 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024900 – Ensembl, May 2017
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  6. ↑ Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J (2004). "Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects". Molecular Aspects of Medicine. 25 (5–6): 495–520. doi:10.1016/j.mam.2004.06.004. PMID   15363638.
  7. 1 2 Jogl G, Tong L (Jan 2003). "Crystal structure of carnitine acetyltransferase and implications for the catalytic mechanism and fatty acid transport". Cell. 112 (1): 113–22. doi: 10.1016/S0092-8674(02)01228-X . PMID   12526798. S2CID   18633987.
  8. ↑ Brown NF, Hill JK, Esser V, Kirkland JL, Corkey BE, Foster DW, McGarry JD (Oct 1997). "Mouse white adipocytes and 3T3-L1 cells display an anomalous pattern of carnitine palmitoyltransferase (CPT) I isoform expression during differentiation. Inter-tissue and inter-species expression of CPT I and CPT II enzymes". The Biochemical Journal. 327 (1): 225–31. doi:10.1042/bj3270225. PMC   1218784 . PMID   9355756.
  9. ↑ Lee J, Ellis JM, Wolfgang MJ (Jan 2015). "Adipose fatty acid oxidation is required for thermogenesis and potentiates oxidative stress-induced inflammation". Cell Reports. 10 (2): 266–279. doi:10.1016/j.celrep.2014.12.023. PMC   4359063 . PMID   25578732.
  10. ↑ Fraser F, Corstorphine, CG, Zammit, VA (May 1997). "Topology of carnitine palmitoyltransferase I in the mitochondrial outer membrane". Biochemical Journal. 323 (3): 711–718. doi: 10.1042/bj3230711 . PMC   1218374 . PMID   1218374.
  11. ↑ Price N, van der Leij F, Jackson V, Corstorphine C, Thomson R, Sorensen A, Zammit V (Oct 2002). "A novel brain-expressed protein related to carnitine palmitoyltransferase I". Genomics. 80 (4): 433–442. doi:10.1006/geno.2002.6845. PMID   12376098.
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  13. ↑ Ezzeddini R, Taghikhani M, Salek Farrokhi A, Somi MH, Samadi N, Esfahani A, Rasaee, MJ (May 2021). "Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and its related clinical significance". Journal of Physiology and Biochemistry. 77 (2): 249–260. doi:10.1007/s13105-021-00791-3. PMID   33730333. S2CID   232300877.
  14. ↑ Morillas M, López-Viñas E, Valencia A, Serra D, Gómez-Puertas P, Hegardt FG, Asins G (May 2004). "Structural model of carnitine palmitoyltransferase I based on the carnitine acetyltransferase crystal". The Biochemical Journal. 379 (Pt 3): 777–784. doi:10.1042/BJ20031373. PMC   1224103 . PMID   14711372.
  15. ↑ Rao JN, Warren GZ, Estolt-Povedano S, Zammit VA, Ulmer TS (2011). "An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A". J Biol Chem. 286 (49): 42545–42554. doi: 10.1074/jbc.M111.306951 . PMC   3234983 . PMID   21990363.
  16. ↑ López-Viñas E, Bentebibel A, Gurunathan C, Morillas M, de Arriaga D, Serra D, Asins G, Hegardt FG, Gómez-Puertas P (Jun 2007). "Definition by functional and structural analysis of two malonyl-CoA sites in carnitine palmitoyltransferase 1A". The Journal of Biological Chemistry. 282 (25): 18212–24. doi: 10.1074/jbc.M700885200 . PMID   17452323.
  17. ↑ Liu H, Zheng G, Treber M, Dai J, Woldegiorgis G (Feb 2005). "Cysteine-scanning mutagenesis of muscle carnitine palmitoyltransferase I reveals a single cysteine residue (Cys-305) is important for catalysis". The Journal of Biological Chemistry. 280 (6): 4524–4531. doi: 10.1074/jbc.M400893200 . PMID   15579906.
  18. ↑ Berg JM, Tymoczo JL, Stryer L, "Biochemistry", 6th edition 2007
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  20. ↑ Shi J, Zhu H, Arvidson DN, Woldegiorgis G (Feb 2000). "The first 28 N-terminal amino acid residues of human heart muscle carnitine palmitoyltransferase I are essential for malonyl CoA sensitivity and high-affinity binding". Biochemistry. 39 (4): 712–717. doi:10.1021/bi9918700. PMID   10651636.
  21. ↑ Abu-Elheiga L, Oh W, Kordari P, Wakil SJ (Sep 2003). "Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high-fat/high-carbohydrate diets". Proceedings of the National Academy of Sciences of the United States of America. 100 (18): 10207–10212. Bibcode:2003PNAS..10010207A. doi: 10.1073/pnas.1733877100 . PMC   193540 . PMID   12920182.
  22. ↑ Ogawa E, Kanazawa M, Yamamoto S, Ohtsuka S, Ogawa A, Ohtake A, Takayanagi M, Kohno Y (2002). "Expression analysis of two mutations in carnitine palmitoyltransferase IA deficiency". Journal of Human Genetics. 47 (7): 342–7. doi: 10.1007/s100380200047 . PMID   12111367.
  23. ↑ Collins SA, Sinclair G, McIntosh S, Bamforth F, Thompson R, Sobol I, Osborne G, Corriveau A, Santos M, Hanley B, Greenberg CR, Vallance H, Arbour L (2010). "Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut". Molecular Genetics and Metabolism. 101 (2–3): 200–204. doi:10.1016/j.ymgme.2010.07.013. PMID   20696606.
  24. ↑ Rasmussen BB, Holmbäck UC, Volpi E, Morio-Liondore B, Paddon-Jones D, Wolfe RR (Dec 2002). "Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle". The Journal of Clinical Investigation. 110 (11): 1687–93. doi:10.1172/JCI15715. PMC   151631 . PMID   12464674.
  25. ↑ McGarry JD, Mills SE, Long CS, Foster DW (Jul 1983). "Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat". The Biochemical Journal. 214 (1): 21–8. doi:10.1042/bj2140021. PMC   1152205 . PMID   6615466.
  26. ↑ Schreurs M, Kuipers F, van der Leij FR (2010). "Regulatory enzymes of mitochondrial beta-oxidation as targets for treatment of the metabolic syndrome". Obesity Reviews. 11 (5): 380–8. doi: 10.1111/j.1467-789X.2009.00642.x . PMID   19694967. S2CID   24954036.
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  28. ↑ Shrivastav S, Zhang L, Okamoto K, Lee H, Lagranha C, Abe Y, Balasubramanyam A, Lopaschuk GD, Kino T, Kopp JB (Sep 2013). "HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity". Molecular Endocrinology. 27 (9): 1564–76. doi:10.1210/me.2012-1370. PMC   3753422 . PMID   23842279.
  29. ↑ Yeung ML, Houzet L, Yedavalli VS, Jeang KT (Jul 2009). "A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing to productive HIV-1 replication". The Journal of Biological Chemistry. 284 (29): 19463–73. doi: 10.1074/jbc.M109.010033 . PMC   2740572 . PMID   19460752.
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