biology

Hydroxymethylglutaryl-CoA synthase

Hydroxymethylglutaryl-CoA synthase is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand Hydroxymethylglutaryl-CoA synthase rather than just read about it. In short: In biochemistry, 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.

Key takeaways

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Reference excerpt

In biochemistry, 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.

The 3 substrates of this enzyme are acetyl-CoA, H2O, and acetoacetyl-CoA, whereas its two products are (S)-3-hydroxy-3-methylglutaryl-CoA and CoA. In humans, two genes encode enzymes of this type, specifically HMGCS1 and HMGCS2.

Classification This enzyme belongs to the family of transferases, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer.

Nomenclature The systematic name of this enzyme class is acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming). Other names in common use include (S)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase, (CoA-acetylating), 3-hydroxy-3-methylglutaryl CoA synthetase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A synthetase, 3-hydroxy-3-methylglutaryl-CoA synthase, 3-hydroxy-3-methylglutaryl-coenzyme A synthase, beta-hydroxy-beta-methylglutaryl-CoA synthase, HMG-CoA synthase, acetoacetyl coenzyme A transacetase, hydroxymethylglutaryl coenzyme A synthase, and hydroxymethylglutaryl coenzyme A-condensing enzyme.

Mechanism HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA.

Biological role This enzyme participates in 3 metabolic pathways: synthesis and degradation of ketone bodies, valine, leucine and isoleucine degradation, and butanoate metabolism.

Species distribution HMG-CoA synthase occurs in eukaryotes, archaea, and certain bacteria.

Eukaryotes In vertebrates, there are two different isozymes of the enzyme (cytosolic and mitochondrial); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other eukaryotes such as insects, plants, and fungi.

Cytosolic The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds.

Mitochondrial The mitochondrial form is responsible for the biosynthesis of ketone bodies. The gene for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region. These elements are responsible for decreased transcription of the message responsible for enzyme synthesis when dietary cholesterol is high in animals: the same is observed for 3-hydroxy-3-methylglutaryl-CoA and the low density lipoprotein receptor.

Bacteria In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes.

Structural studies As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes PDB: 1XPK, PDB: 1XPL, PDB: 1XPM, and PDB: 2P8U.

External links HMG-CoA+synthase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

References

RUDNEY H (1957). "The biosynthesis of beta-hydroxy-beta-methylglutaric acid". J. Biol. Chem. 227 (1): 363–77. doi:10.1016/S0021-9258(18)70822-3. PMID 13449080.

Illustrations

Worked examples

Example 1 — a first encounter with Hydroxymethylglutaryl-CoA synthase

Start with the simplest possible case. Write down what Hydroxymethylglutaryl-CoA synthase claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Hydroxymethylglutaryl-CoA synthase before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Hydroxymethylglutaryl-CoA synthase ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Hydroxymethylglutaryl-CoA synthase

In research: Hydroxymethylglutaryl-CoA synthase appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Hydroxymethylglutaryl-CoA synthase in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Hydroxymethylglutaryl-CoA synthase is common in secondary-school and first-year university syllabi. It links to neighbouring topics EC 2.3.3, Genes on human chromosome 1, Genes on human chromosome 5, so understanding it makes those chapters shorter.
In everyday life: Look for Hydroxymethylglutaryl-CoA synthase outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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Frequently asked questions

What is Hydroxymethylglutaryl-CoA synthase in simple terms?

Why does Hydroxymethylglutaryl-CoA synthase matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Hydroxymethylglutaryl-CoA synthase?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

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