Thiolase

Last updated
Thiolase, N-terminal domain
Identifiers
SymbolThiolase_N
Pfam PF00108
InterPro IPR002155
PROSITE PDOC00092
SCOP2 1pxt / SCOPe / SUPFAM
CDD cd00751
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Thiolase, C-terminal domain
Identifiers
SymbolThiolase_C
Pfam PF02803
InterPro IPR002155
PROSITE PDOC00092
SCOP2 1pxt / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Mevalonate pathway Mevalonate pathway.png
Mevalonate pathway

Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.

Contents

Thiolases are ubiquitous enzymes that have key roles in many vital biochemical pathways, including the beta oxidation pathway of fatty acid degradation and various biosynthetic pathways. [1] Members of the thiolase family can be divided into two broad categories: degradative thiolases (EC 2.3.1.16) and biosynthetic thiolases (EC 2.3.1.9). These two different types of thiolase are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC:2.3.1.9) and 3-ketoacyl-CoA thiolase (EC:2.3.1.16). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as beta-hydroxybutyric acid synthesis or steroid biogenesis.

The formation of a carbon–carbon bond is a key step in the biosynthetic pathways by which fatty acids and polyketide are made. The thiolase superfamily enzymes catalyse the carbon–carbon-bond formation via a thioester-dependent Claisen condensation [2] reaction mechanism. [3]

Function

Thiolases are a family of evolutionarily related enzymes. Two different types of thiolase [4] [5] [6] are found both in eukaryotes and in prokaryotes: acetoacetyl-CoA thiolase (EC 2.3.1.9) and 3-ketoacyl-CoA thiolase (EC 2.3.1.16). 3-ketoacyl-CoA thiolase (also called thiolase I) has a broad chain-length specificity for its substrates and is involved in degradative pathways such as fatty acid beta-oxidation. Acetoacetyl-CoA thiolase (also called thiolase II) is specific for the thiolysis of acetoacetyl-CoA and involved in biosynthetic pathways such as poly beta-hydroxybutyrate synthesis or steroid biogenesis.

In eukaryotes, there are two forms of 3-ketoacyl-CoA thiolase: one located in the mitochondrion and the other in peroxisomes.

There are two conserved cysteine residues important for thiolase activity. The first located in the N-terminal section of the enzymes are involved in the formation of an acyl-enzyme intermediate; the second located at the C-terminal extremity is the active site base involved in deprotonation in the condensation reaction.

Isozymes

EC numberNameAlternate nameIsozymesSubcellular distribution
EC 2.3.1.9 Acetyl-CoA C-acetyltransferase thiolase II;
Acetoacetyl-CoA thiolase		 ACAT1 mitochondrial
ACAT2 cytosolic
EC 2.3.1.16 Acetyl-CoA C-acyltransferase thiolase I;
3-Ketoacyl-CoA thiolase;
β-Ketothiolase
3-KAT		 ACAA1 peroxisomal
ACAA2 mitochondrial
HADHB mitochondrial
EC 2.3.1.154 Propionyl-CoA C2-trimethyltridecanoyltransferase 3-Oxopristanoyl-CoA thiolase
EC 2.3.1.174 3-Oxoadipyl-CoA thiolase β-Ketoadipyl-CoA thiolase
EC 2.3.1.176 Propanoyl-CoA C-acyltransferase Peroxisomal thiolase 2 SCP2 peroxisomal/cytosolic

Mammalian nonspecific lipid-transfer protein (nsL-TP) (also known as sterol carrier protein 2) is a protein which seems to exist in two different forms: a 14 Kd protein (SCP-2) and a larger 58 Kd protein (SCP-x). The former is found in the cytoplasm or the mitochondria and is involved in lipid transport; the latter is found in peroxisomes. The C-terminal part of SCP-x is identical to SCP-2 while the N-terminal portion is evolutionary related to thiolases. [6]

Mechanism

Reaction catalyzed by thiolase Thioalse Reaction Catalysis.gif
Reaction catalyzed by thiolase

Thioesters are more reactive than oxygen esters and are common intermediates in fatty-acid metabolism. [7] These thioesters are made by conjugating the fatty acid with the free SH group of the pantetheine moiety of either coenzyme A (CoA) or acyl carrier protein (ACP).

All thiolases, whether they are biosynthetic or degradative in vivo, preferentially catalyze the degradation of 3-ketoacyl-CoA to form acetyl-CoA and a shortened acyl-CoA species, but are also capable of catalyzing the reverse Claisen condensation reaction (reflecting the negative Gibbs energy change of the degradation, which is independent of the thiolase catalyzing the reaction). It is well established from studies on the biosynthetic thiolase from Z. ramigera that the thiolase reaction occurs in two steps and follows ping-pong kinetics. [8] In the first step of both the degradative and biosynthetic reactions, the nucleophilic Cys89 (or its equivalent) attacks the acyl-CoA (or 3-ketoacyl-CoA) substrate, leading to the formation of a covalent acyl-enzyme intermediate. [9] In the second step, the addition of CoA (in the degradative reaction) or acetyl-CoA (in the biosynthetic reaction) to the acyl–enzyme intermediate triggers the release of the product from the enzyme. [10] Each of the tetrahedral reaction intermediates that occur during transfer of an acetyl group to and from the nucleophilic cysteine, respectively, have been observed in X-ray crystal structures of biosynthetic thiolase from A. fumigatus. [11]

Thiolase Mechanism. The two-step, ping-pong mechanism for the thiolase reaction. Red arrows indicate the biosynthetic reaction; Black arrows trace the degradative reaction. In both directions, the reaction is initiated by the nucleophilic attack of Cys89 on the substrate to form a covalent acetyl-enzyme intermediate. Cys89 is activated for nucleophilic attack by His348, which abstracts the sulfide proton of Cys89. In the second step of both the biosynthetic and degradative reactions, the substrate nucleophilically attacks the acetyl-enzyme intermediate to yield the final product and free enzyme. This nucleophilic attack is activated by Cys378, which abstracts a proton from the substrate. Thiolase Mechanisim.gif
Thiolase Mechanism. The two-step, ping-pong mechanism for the thiolase reaction. Red arrows indicate the biosynthetic reaction; Black arrows trace the degradative reaction. In both directions, the reaction is initiated by the nucleophilic attack of Cys89 on the substrate to form a covalent acetyl–enzyme intermediate. Cys89 is activated for nucleophilic attack by His348, which abstracts the sulfide proton of Cys89. In the second step of both the biosynthetic and degradative reactions, the substrate nucleophilically attacks the acetyl–enzyme intermediate to yield the final product and free enzyme. This nucleophilic attack is activated by Cys378, which abstracts a proton from the substrate.

Structure

Most enzymes of the thiolase superfamily are dimers. However, monomers have not been observed. Tetramers are observed only in the thiolase subfamily and, in these cases, the dimers have dimerized to become tetramers. The crystal structure of the tetrameric biosynthetic thiolase from Zoogloea ramigera has been determined at 2.0 Å resolution. The structure contains a striking and novel ‘cage-like’ tetramerization motif, which allows for some hinge motion of the two tight dimers with respect to each other. The enzyme tetramer is acetylated at Cys89 and has a CoA molecule bound in each of its active-site pockets. [12]

Biological function

In eukaryotic cells, especially in mammalian cells, thiolases exhibit diversity in intracellular localization related to their metabolic functions as well as in substrate specificity. For example, they contribute to fatty-acid β-oxidation in peroxisomes and mitochondria, ketone body metabolism in mitochondria, [13] and the early steps of mevalonate pathway in peroxisomes and cytoplasm. [14] In addition to biochemical investigations, analyses of genetic disorders have made clear the basis of their functions. [15] Genetic studies have identified a three-thiolase system in the yeast Candida tropicalis , which has thiolase activity in peroxisomes, where it may participate in beta oxidation, and in the cytosol, where it participates in the mevalonate pathway. [16] [17] Thiolase is of central importance in key enzymatic pathways such as fatty-acid, steroid and polyketide synthesis. The detailed understanding of its structural biology is of great medical relevance, for example, for a better understanding of the diseases caused by genetic deficiencies of these enzymes and for the development of new antibiotics. [18] Harnessing the complicated catalytic versatility of the polyketide synthases for the synthesis of biologically and medically relevant natural products is also an important future perspective of the studies of the enzymes of this superfamily. [19]

Disease relevance

Mitochondrial acetoacetyl-CoA thiolase deficiency, known earlier as β-ketothiolase deficiency, [20] is an inborn error of metabolism involving isoleucine catabolism and ketone body metabolism. The major clinical manifestations of this disorder are intermittent ketoacidosis but the long-term clinical consequences, apparently benign, are not well documented. Mitochondrial acetoacetyl-CoA thiolase deficiency is easily diagnosed by urinary organic acid analysis and can be confirmed by enzymatic analysis of cultured skin fibroblasts or blood leukocytes. [21]

β-Ketothiolase Deficiency has a variable presentation. Most affected patients present between 5 and 24 months of age with symptoms of severe ketoacidosis. Symptoms can be initiated by a dietary protein load, infection or fever. Symptoms progress from vomiting to dehydration and ketoacidosis. [22] Neutropenia and thrombocytopenia may be present, as can moderate hyperammonemia. Blood glucose is typically normal, but can be low or high in acute episodes. [23] Developmental delay may occur, even before the first acute episode, and bilateral striatal necrosis of the basal ganglia has been seen on brain MRI.

Related Research Articles

<span class="mw-page-title-main">Coenzyme A</span> Coenzyme, notable for its synthesis and oxidation role

Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it (or a thioester) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate (vitamin B5), and adenosine triphosphate (ATP).

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

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

<span class="mw-page-title-main">Enoyl CoA isomerase</span>

Enoyl-CoA-(∆) isomerase (EC 5.3.3.8, also known as dodecenoyl-CoA- isomerase, 3,2-trans-enoyl-CoA isomerase, ∆3 ,∆2 -enoyl-CoA isomerase, or acetylene-allene isomerase, is an enzyme that catalyzes the conversion of cis- or trans-double bonds of coenzyme A bound fatty acids at gamma-carbon to trans double bonds at beta-carbon as below:

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">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 fatty acids. 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 universal biochemical energy carrier.

<span class="mw-page-title-main">HADHA</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase</span> Enzyme

In molecular biology, Beta-ketoacyl-ACP synthase EC 2.3.1.41, is an enzyme involved in fatty acid synthesis. It typically uses malonyl-CoA as a carbon source to elongate ACP-bound acyl species, resulting in the formation of ACP-bound β-ketoacyl species such as acetoacetyl-ACP.

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

Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion pathway, it is no longer associated with having HMG-CoA as a product or as a reactant.

<span class="mw-page-title-main">ACAT1</span> Protein-coding gene in the species Homo sapiens

Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 gene.

<span class="mw-page-title-main">3-hydroxyacyl-CoA dehydrogenase</span> Enzyme

In enzymology, a 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Acetyl-CoA C-acetyltransferase</span> Class of enzymes

In enzymology, an acetyl-CoA C-acetyltransferase is an enzyme that catalyzes the chemical reaction

In enzymology, a [acyl-carrier-protein] S-acetyltransferase is an enzyme that catalyzes the reversible chemical reaction

<span class="mw-page-title-main">Beta-ketoacyl-ACP synthase III</span> Enzyme

In enzymology, a β-ketoacyl-[acyl-carrier-protein] synthase III (EC 2.3.1.180) is an enzyme that catalyzes the chemical reaction

<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:

<span class="mw-page-title-main">Fatty-acyl-CoA synthase</span>

Fatty-acyl-CoA Synthase, or more commonly known as yeast fatty acid synthase, is an enzyme complex responsible for fatty acid biosynthesis, and is of Type I Fatty Acid Synthesis (FAS). Yeast fatty acid synthase plays a pivotal role in fatty acid synthesis. It is a 2.6 MDa barrel shaped complex and is composed of two, unique multi-functional subunits: alpha and beta. Together, the alpha and beta units are arranged in an α6β6 structure. The catalytic activities of this enzyme complex involves a coordination system of enzymatic reactions between the alpha and beta subunits. The enzyme complex therefore consists of six functional centers for fatty acid synthesis.

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

In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthase EC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle, notably oxaloacetate. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.

<span class="mw-page-title-main">ACOX1</span> Protein-coding gene in the species Homo sapiens

Peroxisomal acyl-coenzyme A oxidase 1 is an enzyme that in humans is encoded by the ACOX1 gene.

<span class="mw-page-title-main">ACAA1</span> Protein-coding gene in the species Homo sapiens

3-Ketoacyl-CoA thiolase, peroxisomal also known as acetyl-Coenzyme A acyltransferase 1 is an enzyme that in humans is encoded by the ACAA1 gene.

<span class="mw-page-title-main">Ketoacyl synthase</span> Catalyst for a key step in fatty acid synthesis

Ketoacyl synthases (KSs) catalyze the condensation reaction of acyl-CoA or acyl-acyl ACP with malonyl-CoA to form 3-ketoacyl-CoA or with malonyl-ACP to form 3-ketoacyl-ACP. This reaction is a key step in the fatty acid synthesis cycle, as the resulting acyl chain is two carbon atoms longer than before. KSs exist as individual enzymes, as they do in type II fatty acid synthesis and type II polyketide synthesis, or as domains in large multidomain enzymes, such as type I fatty acid synthases (FASs) and polyketide synthases (PKSs). KSs are divided into five families: KS1, KS2, KS3, KS4, and KS5.

References

  1. ↑ Thompson S, Mayerl F, Peoples OP, Masamune S, Sinskey AJ, Walsh CT (July 1989). "Mechanistic studies on beta-ketoacyl thiolase from Zoogloea ramigera: identification of the active-site nucleophile as Cys89, its mutation to Ser89, and kinetic and thermodynamic characterization of wild-type and mutant enzymes". Biochemistry. 28 (14): 5735–42. doi:10.1021/bi00440a006. PMID   2775734.
  2. ↑ Heath RJ, Rock CO (October 2002). "The Claisen condensation in biology". Nat Prod Rep. 19 (5): 581–96. doi:10.1039/b110221b. PMID   12430724.
  3. ↑ Haapalainen AM, Meriläinen G, Wierenga RK (January 2006). "The thiolase superfamily: condensing enzymes with diverse reaction specificities". Trends Biochem. Sci. 31 (1): 64–71. doi:10.1016/j.tibs.2005.11.011. PMID   16356722.
  4. ↑ Baker ME, Billheimer JT, Strauss JF (November 1991). "Similarity between the amino-terminal portion of mammalian 58-kD sterol carrier protein (SCPx) and Escherichia coli acetyl-CoA acyltransferase: evidence for a gene fusion in SCPx". DNA Cell Biol. 10 (9): 695–8. doi:10.1089/dna.1991.10.695. PMID   1755959.
  5. ↑ Yang SY, Yang XY, Healy-Louie G, Schulz H, Elzinga M (June 1990). "Nucleotide sequence of the fadA gene. Primary structure of 3-ketoacyl-coenzyme A thiolase from Escherichia coli and the structural organization of the fadAB operon". J. Biol. Chem. 265 (18): 10424–9. PMID   2191949.
  6. 1 2 Igual JC, González-Bosch C, Dopazo J, Pérez-Ortín JE (August 1992). "Phylogenetic analysis of the thiolase family. Implications for the evolutionary origin of peroxisomes". J. Mol. Evol. 35 (2): 147–55. doi:10.1007/BF00183226. PMID   1354266. S2CID   39746646.
  7. ↑ Enzymatic reaction mechanisms. San Francisco: W. H. Freeman. 1979. ISBN   978-0-7167-0070-8.
  8. ↑ Masamune, Satoru; Walsh, Christopher T.; Gamboni, Remo; Thompson, Stuart; Davis, Jeffrey T.; Williams, Simon F.; Peoples, Oliver P.; Sinskey, Anthony J.; Walsh, Christopher T. (1989). "Bio-Claisen condensation catalyzed by thiolase from Zoogloea ramigera. Active site cysteine residues". J. Am. Chem. Soc. 111 (5): 1879, 1991. doi:10.1021/ja00187a053.
  9. ↑ Gilbert HF, Lennox BJ, Mossman CD, Carle WC (July 1981). "The relation of acyl transfer to the overall reaction of thiolase I from porcine heart". J. Biol. Chem. 256 (14): 7371–7. PMID   6114098.
  10. ↑ Mathieu M, Modis Y, Zeelen JP, et al. (October 1997). "The 1.8 A crystal structure of the dimeric peroxisomal 3-ketoacyl-CoA thiolase of Saccharomyces cerevisiae: implications for substrate binding and reaction mechanism". J. Mol. Biol. 273 (3): 714–28. doi: 10.1006/jmbi.1997.1331 . PMID   9402066.
  11. ↑ Marshall, Andrew C.; Bond, Charles S.; Bruning, John B. (January 25, 2018). "Structure of Aspergillus fumigatus Cytosolic Thiolase: Trapped Tetrahedral Reaction Intermediates and Activation by Monovalent Cations". ACS Catalysis. 8 (3): 1973–1989. doi:10.1021/acscatal.7b02873. hdl: 2440/113865 .
  12. ↑ Modis Y, Wierenga RK (October 1999). "A biosynthetic thiolase in complex with a reaction intermediate: the crystal structure provides new insights into the catalytic mechanism". Structure. 7 (10): 1279–90. doi: 10.1016/S0969-2126(00)80061-1 . PMID   10545327.
  13. ↑ Middleton B (April 1973). "The oxoacyl-coenzyme A thiolases of animal tissues". Biochem. J. 132 (4): 717–30. doi:10.1042/bj1320717. PMC   1177647 . PMID   4721607.
  14. ↑ Hovik R, Brodal B, Bartlett K, Osmundsen H (June 1991). "Metabolism of acetyl-CoA by isolated peroxisomal fractions: formation of acetate and acetoacetyl-CoA". J. Lipid Res. 32 (6): 993–9. PMID   1682408.
  15. ↑ Middleton B, Bartlett K (March 1983). "The synthesis and characterisation of 2-methylacetoacetyl coenzyme A and its use in the identification of the site of the defect in 2-methylacetoacetic and 2-methyl-3-hydroxybutyric aciduria". Clin. Chim. Acta . 128 (2–3): 291–305. doi:10.1016/0009-8981(83)90329-7. PMID   6133656.
  16. ↑ Kanayama N, Ueda M, Atomi H, Tanaka A (February 1998). "Genetic evaluation of physiological functions of thiolase isoenzymes in the n-alkalane-assimilating yeast Candida tropicalis". J. Bacteriol. 180 (3): 690–8. doi:10.1128/JB.180.3.690-698.1998. PMC   106940 . PMID   9457876.
  17. ↑ Ueda M, Kanayama N, Tanaka A (2000). "Genetic evaluation of peroxisomal and cytosolic acetoacetyl-CoA thiolase isozymes in n-alkane-assimilating diploid yeast, Candida tropicalis". Cell Biochemistry and Biophysics. 32 (Spring): 285–290. doi:10.1385/cbb:32:1-3:285. PMID   11330060.
  18. ↑ Price AC, Choi KH, Heath RJ, Li Z, White SW, Rock CO (March 2001). "Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism". J. Biol. Chem. 276 (9): 6551–9. doi: 10.1074/jbc.M007101200 . PMID   11050088.
  19. ↑ Keatinge-Clay AT, Maltby DA, Medzihradszky KF, Khosla C, Stroud RM (September 2004). "An antibiotic factory caught in action". Nat. Struct. Mol. Biol. 11 (9): 888–93. doi:10.1038/nsmb808. PMID   15286722. S2CID   12394083.
  20. ↑ Daum RS, Lamm PH, Mamer OA, Scriver CR (December 1971). "A "new" disorder of isoleucine catabolism". Lancet. 2 (7737): 1289–90. doi:10.1016/S0140-6736(71)90605-2. PMID   4143539.
  21. ↑ Mitchell GA, Fukao T (2001). "Inborn errors of ketone body metabolism". In Scriver CR, Beaudet AL, Sly WS, Valle D (eds.). The metabolic & molecular bases of inherited disease. New York: McGraw-Hill. pp. 2326–2356. ISBN   978-0-07-913035-8.
  22. ↑ Hillman RE, Keating JP (February 1974). "Beta-ketothiolase deficiency as a cause of the "ketotic hyperglycinemia syndrome"". Pediatrics. 53 (2): 221–5. PMID   4812006.
  23. ↑ Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA (August 1979). "Acetoacetyl CoA thiolase deficiency: a cause of severe ketoacidosis in infancy simulating salicylism". J. Pediatr. 95 (2): 228–33. doi:10.1016/S0022-3476(79)80658-7. PMID   36452.


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