D-bifunctional protein deficiency

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D-bifunctional protein deficiency
Other names17β-hydroxysteroid dehydrogenase IV deficiency
Specialty Medical genetics

D-Bifunctional protein deficiency is an autosomal recessive peroxisomal fatty acid oxidation disorder. Peroxisomal disorders are usually caused by a combination of peroxisomal assembly defects or by deficiencies of specific peroxisomal enzymes. The peroxisome is an organelle in the cell similar to the lysosome that functions to detoxify the cell. Peroxisomes contain many different enzymes, such as catalase, and their main function is to neutralize free radicals and detoxify drugs. For this reason peroxisomes are ubiquitous in the liver and kidney. D-BP deficiency is the most severe peroxisomal disorder, [1] often resembling Zellweger syndrome. [2]

Contents

Characteristics of the disorder include neonatal hypotonia and seizures, occurring mostly within the first month of life, as well as visual and hearing impairment. [3] Other symptoms include severe craniofacial disfiguration, psychomotor delay, and neuronal migration defects. Most onsets of the disorder begin in the gestational weeks of development and most affected individuals die within the first two years of life.

Classification

DBP deficiency can be divided into three types: [4]

Type I deficient patients showed a large structural modification to the D-BP as a whole. Most of these individuals showed either a deletion or an insertion resulting in a frameshift mutation. Type II and III patients showed small scale changes in the overall structure of D-BP[6]. Amino acid changes in the catalytic domains or those in contact with substrate or cofactors were the main cause of these variations of D-BP deficiency. Other amino acid changes were seen to alter the dimerization of the protein, leading to improper folding. Many mutations have been found in the gene coding for D-BP ( HSD17B4 ) on the q arm two of chromosome five (5q23.1) in Homo sapiens, most notably individuals homozygous for a missense mutation (616S). [4]

D-BP Protein

The D-bifunctional protein is composed of three enzymatic domains: the N-terminal short chain alcohol dehydrogenase reductase (SDR), central hydratase domain, and the C-terminal sterol carrier protein 2 (SDR). [1]

The DBP protein (79kDa) also known as "multifunctional protein 2", "multifunctional enzyme 2", or "D-peroxisomal bifunctional"enzyme", catalyzes the second and third steps of peroxisomal β-oxidation of fatty acids and their derivatives. [4]

A non-functional D-BP protein results in the abnormal accumulation of long chain fatty acids and bile acid intermediates. The D-BP protein contains a peroxisomal targeting signal 1 (PTS1) unit at the C-terminus allowing for its transport into peroxisomes by the PTS1 receptor. Inside the peroxisomes, the D-BP protein is partially cleaved exclusively between the SDR and hydratase"domains. [1]

DBP is a stereospecific enzyme; hydratase domain forms only (R)-hydroxy-acyl-CoA intermediates from trans-2-enoyl-CoAs. [4] D-BP is expressed throughout the entire human body, with the highest mRNA levels in the liver and brain. The hydrogenase and hydratase units of DBP exist as dimers, necessary for correct folding and therefore function of the enzyme.

Genetic

The D-BP gene (HSD17B4), found on the long arm of chromosome 5, consists of 24 exons and 23 introns and is over 100kb in size. Exons 1-12 code for the SDR domain, 12-21 for the hydratase domain, and 21-24 for the SCP2 domain. Transcription is regulated at 400 basepairs upstream of the transcription start site. [1]

The missense mutation G16S is the most common mutation that leads to D-BP deficiency. In a 2006 study in which 110 patients were tested, 28 had this frameshift mutation. The second most frequent mutation was the missense mutation N457Y which was seen in 13 of the 110 patients. Type I patients showed only deletions, insertions, and nonsense mutations were identified, most leading to shortened polypeptides. Most type II patients show missense mutations in D-BP hydratase unit as well as some in-frame deletions. Type III"individuals commonly show missense mutations in the coding region of the dehydrogenase domain. [4]

Chemistry

Enzymatic activity of D-BP fails if the protein cannot effectively bind the cofactor NAD+, as shown in the G16S mutation. Glycine 16 forms a short loop and creates a hole for the adenine ring of NAD+ to enter. Other amino acid side chains alter the shape of this loop due to steric hindrance, and prevent proper NAD+ binding. Other mutations that exist are due to incorrect polypeptide folding. L405 (leucine located at residue 405) located in the substrate binding domain of the hydratase 2 unit, plays an important role in binding CoA ester moiety. One mutation seen in D-BP deficiency patients is caused by a leucine to proline substitution. This breaks the hydrophobic interactions necessary for proper substrate binding with CoA esters. [4]

Diagnosis

The most common clinical observations of patients with D-bifunctional protein deficiency include hypotonia, facial and skull dysmorphism, neonatal seizures, and neuronal demyelination. [5] High levels of branched fatty acids, such as pristinic acid, bile acid intermediates, and other D-BP substrates are seen to exist. Reduced pristinic acid β-oxidation is a common indicator of D-BP deficiency. [1] D-BP can be distinguished from Zellweger Syndrome by normal plasmalogen synthesis. Recent studies in D-BP knockout mice show compensatory upregulation of other peroxisomal enzymes in absence of D-BP such as palmitoyl-CoA oxidase, peroxisomal thiolase, and branched chain acyl-CoA oxidase. [1]

Related Research Articles

<span class="mw-page-title-main">Peroxisome</span> Type of organelle

A peroxisome (IPA:[pɛɜˈɹɒksɪˌsoʊm]) is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen peroxide (H2O2) is then formed. Peroxisomes owe their name to hydrogen peroxide generating and scavenging activities. They perform key roles in lipid metabolism and the reduction of reactive oxygen species.

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

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:

<span class="mw-page-title-main">Zellweger syndrome</span> Congenital disorder of nervous system

Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.

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">Mitochondrial trifunctional protein deficiency</span> Medical condition

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

Refsum disease is an autosomal recessive neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991). Refsum disease typically is adolescent onset and is diagnosed by above average levels of phytanic acid. Humans obtain the necessary phytanic acid primarily through diet. It is still unclear what function phytanic acid plays physiologically in humans, but has been found to regulate fatty acid metabolism in the liver of mice.

<span class="mw-page-title-main">ACADS</span> Protein-coding gene in humans

Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene is associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

<span class="mw-page-title-main">Peroxisomal disorder</span> Medical condition

Peroxisomal disorders represent a class of medical conditions caused by defects in peroxisome functions. This may be due to defects in single enzymes important for peroxisome function or in peroxins, proteins encoded by PEX genes that are critical for normal peroxisome assembly and biogenesis.

<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">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">2,4 Dienoyl-CoA reductase</span> Class of enzymes

2,4 Dienoyl-CoA reductase also known as DECR1 is an enzyme which in humans is encoded by the DECR1 gene which resides on chromosome 8. This enzyme catalyzes the following reactions

<span class="mw-page-title-main">Thiolase</span> Enzymes

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.

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

ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.

Infantile Refsum disease (IRD) is a rare autosomal recessive congenital peroxisomal biogenesis disorder within the Zellweger spectrum. These are disorders of the peroxisomes that are clinically similar to Zellweger syndrome and associated with mutations in the PEX family of genes. IRD is associated with deficient phytanic acid catabolism, as is adult Refsum disease, but they are different disorders that should not be confused.

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

In enzymology, a phytanoyl-CoA dioxygenase (EC 1.14.11.18) is an enzyme that catalyzes the chemical reaction

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

α-Methylacyl-CoA racemase is an enzyme that in humans is encoded by the AMACR gene. AMACR catalyzes the following chemical reaction:

<span class="mw-page-title-main">HSD17B4</span> Protein-coding gene in the species Homo sapiens

D-bifunctional protein (DBP), also known as peroxisomal multifunctional enzyme type 2 (MFP-2), as well as 17β-hydroxysteroid dehydrogenase type IV is a protein that in humans is encoded by the HSD17B4 gene. It's an alcohol oxidoreductase, specifically 17β-Hydroxysteroid dehydrogenase. It is involved in fatty acid β-oxidation and steroid metabolism.

<span class="mw-page-title-main">ABCD3</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette sub-family D member 3 is a protein that in humans is encoded by the ABCD3 gene.

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

Hydroxyacyl-Coenzyme A dehydrogenase (HADH) is an enzyme which in humans is encoded by the HADH gene.

EHHADH is a human gene that encodes for a bifunctional enzyme and is one of the four enzymes of the peroxisomal beta-oxidation pathway. Mutations of the gene are a cause of peroxisomal disorders such as Zellweger syndrome.

References

  1. 1 2 3 4 5 6 Möller G, van Grunsven EG, Wanders RJ, Adamski J (January 2001). "Molecular basis of D-bifunctional protein deficiency". Mol. Cell. Endocrinol. 171 (1–2): 61–70. doi:10.1016/s0303-7207(00)00388-9. PMID   11165012. S2CID   29712091.
  2. ↑ Itoh M, Suzuki Y, Akaboshi S, Zhang Z, Miyabara S, Takashima S (March 2000). "Developmental and pathological expression of peroxisomal enzymes: their relationship of D-bifunctional protein deficiency and Zellweger syndrome". Brain Res. 858 (1): 40–7. doi:10.1016/S0006-8993(99)02423-3. PMID   10700594. S2CID   11224543.
  3. ↑ Buoni S, Zannolli R, Waterham H, Wanders R, Fois A (January 2007). "D-bifunctional protein deficiency associated with drug resistant infantile spasms". Brain Dev. 29 (1): 51–4. doi:10.1016/j.braindev.2006.06.004. PMID   16919904. S2CID   617635.
  4. 1 2 3 4 5 6 Ferdinandusse S, Ylianttila MS, Gloerich J, Koski MK, Oostheim W, Waterham HR, Hiltunen JK, Wanders RJ, Glumoff T (January 2006). "Mutational spectrum of D-bifunctional protein deficiency and structure-based genotype-phenotype analysis". Am. J. Hum. Genet. 78 (1): 112–24. doi:10.1086/498880. PMC   1380208 . PMID   16385454.
  5. ↑ van Grunsven EG, Mooijer PA, Aubourg P, Wanders RJ (August 1999). "Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional protein deficiency". Hum. Mol. Genet. 8 (8): 1509–16. doi: 10.1093/hmg/8.8.1509 . PMID   10400999.
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