DOPA decarboxylase

From Proteopedia

proteopedia linkproteopedia link

Revision as of 00:00, 25 June 2011 (edit) Brittany Todd (Talk | contribs) ← Previous diff		Revision as of 00:15, 25 June 2011 (edit) (undo) Brittany Todd (Talk | contribs) Next diff →
Line 15:		Line 15:
	[[image:dopastructure.png|thumb|left|400px|'''large domain, small domain, and N-terminal domain''']]		[[image:dopastructure.png|thumb|left|400px|'''large domain, small domain, and N-terminal domain''']]
	===DOPA Decarboxylase===		===DOPA Decarboxylase===
		+	====Primary Structure====
		+	The amino acid sequence of a proteins polypeptide chain is referred to as its '''primary structure'''. Each polypeptide chain of DOPA decarboxylase is composed of 486 amino acids that ultimately encode the three-dimensional structure of the monomeric protein.
		+	====Secondary Structure====
		+	The formation of secondary structural elements (like α helices and β sheets) arise in response to the hydrophobic effect and the need to neutralize main-chain polar groups by '''hydrogen bonding'''.
	DOPA decarboxylase is a homodimeric enzyme, with each monomer composed of three distinct domains. The large domain contains the PLP-binding site, and consists of a seven stranded mixed β sheet that is surrounded by eight α helices, resulting in a typical <scene name='DOPA_decarboxylase/Alphabeta_fold/1'>α/β fold</scene>, the most regular and common tertiary structure (recall that α helices and β strands typically alternate in this fold, generating an outer layer of α helices and an inner layer of β sheets). [[image:dopadecarb.png|thumb|left|200px|'''DOPA Decarboxylase''']]The C-terminal domain is comprised of a four-stranded anti-parallel β sheet that has three α helices packed against the face opposite to the large domain. Although the aforementioned domains exist in all members of this family of PLP-dependent enzymes, including bacterial [http://en.wikipedia.org/wiki/Ornithine_decarboxylase ''ornithine decarboxylase''] (OrnDC) and [http://en.wikipedia.org/wiki/2,2-dialkylglycine_decarboxylase_(pyruvate) ''dialkylglycine decarboxylase''] (DGD), the <scene name='Sandbox/N-terminal_domain/2'>N-terminal domain</scene> is unique to DOPA decarboxylase, and is a representative case of '''domain swapping'''. This domain is composed of two parallel helices linked by an extended strand, which essentially lies like a flap over the second subunit. The N-terminal domain of one monomer packs on top of the other monomer, resulting in an extended dimer interface, and thus it is most likely stable only in the dimeric form of the enzyme.		DOPA decarboxylase is a homodimeric enzyme, with each monomer composed of three distinct domains. The large domain contains the PLP-binding site, and consists of a seven stranded mixed β sheet that is surrounded by eight α helices, resulting in a typical <scene name='DOPA_decarboxylase/Alphabeta_fold/1'>α/β fold</scene>, the most regular and common tertiary structure (recall that α helices and β strands typically alternate in this fold, generating an outer layer of α helices and an inner layer of β sheets). [[image:dopadecarb.png|thumb|left|200px|'''DOPA Decarboxylase''']]The C-terminal domain is comprised of a four-stranded anti-parallel β sheet that has three α helices packed against the face opposite to the large domain. Although the aforementioned domains exist in all members of this family of PLP-dependent enzymes, including bacterial [http://en.wikipedia.org/wiki/Ornithine_decarboxylase ''ornithine decarboxylase''] (OrnDC) and [http://en.wikipedia.org/wiki/2,2-dialkylglycine_decarboxylase_(pyruvate) ''dialkylglycine decarboxylase''] (DGD), the <scene name='Sandbox/N-terminal_domain/2'>N-terminal domain</scene> is unique to DOPA decarboxylase, and is a representative case of '''domain swapping'''. This domain is composed of two parallel helices linked by an extended strand, which essentially lies like a flap over the second subunit. The N-terminal domain of one monomer packs on top of the other monomer, resulting in an extended dimer interface, and thus it is most likely stable only in the dimeric form of the enzyme.
	[[image:super1.png|thumb|right|200px|'''DOPA decarboxylase superimposed on aspartate aminotransferase''']][[image:super2.png|thumb|right|200px|'''DOPA decarboxylase superimposed on aspartate aminotransferase with the large subunit 7-stranded β sheet highlighted''']]		[[image:super1.png|thumb|right|200px|'''DOPA decarboxylase superimposed on aspartate aminotransferase''']][[image:super2.png|thumb|right|200px|'''DOPA decarboxylase superimposed on aspartate aminotransferase with the large subunit 7-stranded β sheet highlighted''']]

---

Revision as of 00:15, 25 June 2011

Contents 1 Introduction 2 PLP-Dependent Enzymes 2.1 Overview 2.2 The Aspartate Aminotransferase Family 2.3 DOPA Decarboxylase 2.3.1 Primary Structure 2.3.2 Secondary Structure 3 Function 3.1 The Active Site 3.2 DOPA decarboxylase 3.3 Substrate Binding 4 Classification 4.1 SCOP 4.2 CATH 5 3D structures of DOPA decarboxylase 6 References

Introduction

---

spinqualitylabelsall models PDB ID 1js3 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
1js3, resolution 2.25Å ()
Ligands:	, ,
Activity:	Aromatic-L-amino-acid decarboxylase, with EC number 4.1.1.28
Related:	1js6
Structural annotation: Resources: CATH : 1Js3A01, 1Js3A03, 1Js3A02, 1Js3B03, 1Js3B02, 1Js3B01 InterPro : Ipr010977, Ipr002129, Ipr015421, Ipr015424, Ipr015422 Pfam : PF00282 SCOP : d1js3a_, d1js3b_ UniProt : P80041
Functional annotation: Biological process: carboxylic acid metabolic process amino acid and derivative metabolic process catecholamine biosynthetic process Molecular function: lyase activity carboxy-lyase activity catalytic activity pyridoxal phosphate binding aromatic-L-amino-acid decarboxylase activity
Evolutionary conservation: Toggle Conservation Colors: Rows = identical sequences: Further Information: Caveats, Explanation, Complete Results at ConSurfDB
Resources:	FirstGlance, OCA, RCSB, PDBsum
Coordinates:	save as pdb, mmCIF, xml

DOPA decarboxylase (DDC, aromatic L-amino acid decarboxylase, tryptophan decarboxylase, 5-hydroxytryptophan decarboxylase, AAAD) is an approximately 104 kDa protein that belongs to the aspartate aminotransferase family (fold type 1) of PLP-dependent (vitamin B6-dependent) enzymes. The catalytically active form of the enzyme exists as a homodimer, typical of this class of enzymes.^[1] The homodimeric form of the enzyme purified from sus scrofa is shown in complex with the inhibitor carbidopa to the right.

DOPA decarboxylase is responsible for the synthesis of dopamine and serotonin from L-DOPA and L-5-hydroxytryptophan, respectively. Due to its role in neurotransmitter synthesis, DOPA decarboxylase has been implicated in Parkinson's disease, a disease thought to be the result of the degeneration of dopamine-producing cells in the brain. Currently, treatment for the disease is aimed at DOPA decarboxylase inhibition. Since dopamine cannot cross the blood-brain barrier, it cannot be used to directly treat Parkinson's disease. Thus, exogenously administered L-DOPA is the primary treatment for patients suffering from this neurodegenerative disease. Unfortunately, DOPA decarboxylase rapidly converts L-DOPA to dopamine in the blood stream, with only a small percentage reaching the brain. By inhibiting the enzyme, greater amounts of exogenously administered L-DOPA can reach the brain, where it can then be converted to dopamine. ^[2]

PLP-Dependent Enzymes

---

Overview

Pyridoxal-5'-phosphate (PLP), the biologically active phosphorylated derivative of vitamin B6, is a versatile and abundant cofactor to a variety of enzymes in all organisms. Almost all PLP-dependet enzymes function in pathways associated with amino compounds, primarily amino acid metabolism. The reactions carried out by these enzymes include transamination, deamination, decarboxylation', racemization, and eliminations and replacements at the β and γ atoms of amino acid side chains. The versatility of this superfamily of enzymes can be attributed to the ability of PLP to covalently bind the substrate and then function as an electrophilic catalyst. In spite of the functional variety of these enzymes, there exist only five structural classes: the aspartate amino transferase family, the tryptophan synthase β family, the alanine racemase family, the D-amino acid family, and the glycogen phosphorylase family. ^{[3] [1]}

The Aspartate Aminotransferase Family

This family of PLP-dependent enzymes is also referred to as fold-type I, with aspartate aminotransferase serving as the prototype. It is the most common structure of the five classes of PLP-dependent enzymes. This fold it is found in a variety of aminotransferases and decarboxylases, amongst them DOPA decarboxylase. PLP-dependent enzymes belonging to this family are catalytically active as homodimers and share a common, well-characterized structure, despite low-sequence identity. Each subunit has a large domain and a small domain. The central feature of the large domain is a seven-stranded β sheet. The small domain has either a three or four-stranded β sheet that is surrounded by α helices on one side. The cofactor PLP is covalently attached to a lysine residue in the large domain and is anchored in a way that allows the aromatic ring of PLP to pack against neighboring β strands. The active site is located in a cleft between the two domains at the interface between the two subunits. Thus, enzymes of fold-type I have residues from both domains and both subunits involved in PLP-binding.

DOPA Decarboxylase

Primary Structure

The amino acid sequence of a proteins polypeptide chain is referred to as its primary structure. Each polypeptide chain of DOPA decarboxylase is composed of 486 amino acids that ultimately encode the three-dimensional structure of the monomeric protein.

Secondary Structure

The formation of secondary structural elements (like α helices and β sheets) arise in response to the hydrophobic effect and the need to neutralize main-chain polar groups by hydrogen bonding.

DOPA decarboxylase is a homodimeric enzyme, with each monomer composed of three distinct domains. The large domain contains the PLP-binding site, and consists of a seven stranded mixed β sheet that is surrounded by eight α helices, resulting in a typical , the most regular and common tertiary structure (recall that α helices and β strands typically alternate in this fold, generating an outer layer of α helices and an inner layer of β sheets). The C-terminal domain is comprised of a four-stranded anti-parallel β sheet that has three α helices packed against the face opposite to the large domain. Although the aforementioned domains exist in all members of this family of PLP-dependent enzymes, including bacterial ornithine decarboxylase (OrnDC) and dialkylglycine decarboxylase (DGD), the is unique to DOPA decarboxylase, and is a representative case of domain swapping. This domain is composed of two parallel helices linked by an extended strand, which essentially lies like a flap over the second subunit. The N-terminal domain of one monomer packs on top of the other monomer, resulting in an extended dimer interface, and thus it is most likely stable only in the dimeric form of the enzyme.

Function

---

The Active Site

The active site of DOPA decarboxylase is located in a cleft at the between the two subunits of the dimer, like all PLP-dependent enzymes of the aspartate aminotransferase family. Since it is at the interface, residues from both domains and both subunits are involved in cofactor binding, although the active site is composed of residues mainly from one monomer. The is composed of several key residues. serves to bind PLP via a Schiff base linkage. As well, a salt bridge exists between the carboxyl group of and a pyridine nitrogen of PLP to further stabilize intermediates.

The binds to the enzyme by forming a hydrazone linkage.

DOPA decarboxylase

Substrate Binding

Classification

---

SCOP

DOPA decarboxylase is classified in the following manner using SCOP:

1. Class: alpha and beta proteins (α/β)
2. Fold: PLP-dependent transferase-like
3. Superfamily: PLP-dependent transferases
4. Family: Pyridoxal-dependent decarboxylase
5. Domain: DOPA decarboxylase

CATH

DOPA decarboxylase is classified in the following manner using CATH:

• large domain

1. Class: alpha beta
2. Architecture: 3-layer sandwich
3. Topology: Aspartate aminotransferase

• small domain

1. Class: alpha beta
2. Architecture: alpha-beta complex
3. Topology: Aspartate aminotransferase

• N-terminal domain

1. Class: mainly alpha
2. Architecture: up-down bundle
3. Topology: dopa decarboxylase

3D structures of DOPA decarboxylase

3k40 – DDC – Drosophila melanogaster
1js3 – pDDC + inhibitor – pig
1js6 - pDDC

References

---

1. ↑ ^{1.0 1.1} Schneider G, Kack H, Lindqvist Y. The manifold of vitamin B6 dependent enzymes. Structure. 2000 Jan 15;8(1):R1-6. PMID:10673430
2. ↑ Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN. Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Biol. 2001 Nov;8(11):963-7. PMID:11685243 doi:http://dx.doi.org/10.1038/nsb1101-963
3. ↑ Percudani R, Peracchi A. A genomic overview of pyridoxal-phosphate-dependent enzymes. EMBO Rep. 2003 Sep;4(9):850-4. PMID:12949584 doi:http://dx.doi.org/10.1038/sj.embor.embor914