3-Hydroxy-3-methylglutaryl-CoA lyase (or

HMG-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of ...

lyase) is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

( that in human is encoded by the HMGCL

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

located on

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...

. It is a key enzyme in

ketogenesis Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under ...

(

ketone body Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...

formation). It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

Structure

The HMGCL gene encodes a 34.5-kDa protein that is localized to the mitochondrion and peroxisome. Multible

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some iso ...

s of the proteins are known due to alternative splicing. The major isoform (isoform 1) is most highly expressed in the liver whereas isoform 2 is found in energy-demanding tissues including the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, and skeletal muscle. Structure of the HMGCL protein has been resolved by

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

at 2.1-Å resolution, and reveals that the protein may function as a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ...

. Substrate access to the active site of the HMGCL enzyme involves substrate binding across a cavity located at the C-terminal end of a beta barrel structure. In addition, the lysine 48 residue which is mutated in patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency is also found to be necessary for substrate binding.

Function

The HMGCL protein plays an essential role in breaking down dietary proteins and fats for energy. It catalyzes the reaction: :(''S'')-3-hydroxy-3-methylglutaryl-CoA = acetyl-CoA + acetoacetate and requires a

divalent In chemistry, the valence (US spelling) or valency (British spelling) of an chemical element, element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules. Description The combining capacity, ...

metal ion as co-factor. The enzyme is required for

in the liver, and is also responsible for processing the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

leucine Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- ...

inside the mitochondrion Deficiency HMG-CoA lyase deficiency causes hypoketotic hypoglycemia similar to that is caused by HMGCS2 mutations but also leads to organic acid accumulation and metabolic acidosis due to altered leucine metabolism. This disorder can be mistaken for Reye syndrome because of the symptoms of vomiting, lethargy, and convulsions.

Clinical significance

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

s in the ''HMGCL''

cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD), a rare autosomal recessive

inborn error of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances ( substr ...

characterized by disruption of

and L-leucine catabolism. To-date more than 30 different mutations including

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

s of different residues have been associated with patients with HMGCLD in diverse families and ethnicities. HMGCLD typically presents in the first year of the patient's life after a fasting period. Clinical acute symptoms include vomiting,

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s, metabolic

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describes ...

, hypoketotic

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

, and lethargy.

Interactions

HMGCL interacts with itself to form

homodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

s and homotetramers. It is also shown in

yeast two-hybrid Two-hybrid screening (originally known as yeast two-hybrid system or Y2H) is a molecular biology technique used to discover protein–protein interactions (PPIs) and protein–DNA interactions by testing for physical interactions (such as bind ...

experiments to interact with

DNAJA1 DnaJ homolog subfamily A member 1 is a protein that in humans is encoded by the ''DNAJA1'' gene. Interactions DNAJA1 has been shown to interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex ...

References

External links

* EC 4.1.3 {{lyase-stub