Amidohydrolase Superfamily

Abstract

The amidohydrolase superfamily is a structure‐based cluster of enzymes that contain a sturdy and versatile triosephosphate isomerase (TIM)‐like (β/α)8‐barrel fold embracing the catalytic active site. To date, the amidohydrolase superfamily has grown into one of the largest families of enzymes, with tens of thousand of members catalysing a wide range of hydrolytic and nonhydrolytic metabolic reactions which are important in amino acid and nucleotide metabolism as well as biodegradation of agricultural and industrial compounds. Previously, the presence of a mono‐ or dinuclear d‐block metal cofactor in the active site was thought to be one of the main characteristics of the members in this superfamily. However, recently new members containing a trinuclear metal cofactors or no cofactor at all were discovered. It has become apparent that activating a well‐ordered water molecule by an active site residue for nucleophilic attack on the organic substrate is a common mechanistic feature for all members of the superfamily.

Key Concepts:

  • Amidohydrolase superfamily is one of the largest enzyme superfamilies performing a wide array of catalytic reactions.

  • All members in the family employ a TIM‐barrel structural fold, although some of the amidohydrolase superfamily members present an imperfect barrel.

  • The vast majority, but not all, of the enzymes in this superfamily are metalloenzymes.

  • The hallmark of the catalytic mechanisms shared by these enzymes is to use an activated water molecule to attack the organic substrate.

  • The catalytic centre is diverse, with one, two, three or zero metal ion(s).

Keywords: amidohydrolase; metal cofactor; TIM‐barrel structural fold; enzymology; evolution

Figure 1.

Metal cofactor and the TIM‐like parallel barrel core in ADA (PDB entry 1A4M). The metal ion is depicted as CPK sphere, metal ligands are shown in sticks and the propeller structural fold is highlighted in blue colour in the representation. Substrate analogue 6‐hydroxy‐1,6‐dihydro purine nucleoside is represented in scaled ball and stick.

Figure 2.

The crystal structures of (a) BmulJ_04915 (PDB entry 4DNM, cofactor free), (b) ADA (PDB entry 1A4M, mononuclear metal cofactor), (c) PTE (PDB entry 1HZY, dinuclear metal cofactor) and (d) HPP (PDB entry 4GC3, trinuclear metal cofactor). Metal ions are shown as yellow spheres. Metal ligand residues are shown in sticks and the propeller structural fold is highlighted in purple.

Figure 3.

An imperfect TIM‐barrel exhibited in the structure of AMPD in complex with coformycin 5′‐phosphate (ball and stick) (PDB entry 2A3L). The inset highlights the distorted barrel and the zinc ion (CPK sphere).

Figure 4.

Hydrolytic and nonhydrolytic reactions catalysed by the structurally characterised members of the amidohydrolase superfamily.

Figure 5.

Chemical reaction catalysed by 4‐oxalomesaconate hydratase (OMAH). A water molecule is added across the 4,5‐carbon double bond.

Figure 6.

A working model of α‐amino‐β‐carboxymuconate‐ϵ‐semialdehyde decarboxylase (ACMSD) catalytic cycle for a nonhydrolytic C–C bond cleavage. Arg* represents a conserved arginine residue intruded to catalytic centre from a neighbouring subunit of the homodimeric protein.

Figure 7.

The proposed catalytic mechanism of dihydroorotase (DHO). DHO contains a dinuclear metal centre and catalyses a ring opening reaction using dihydroorotate as substrate.

Figure 8.

The mechanistic model for a trinucler zinc centre‐mediated l‐histidinol phosphate phosphatase (HPP) reaction. l‐Histidinol and inorganic phosphate are the two reaction products.

Figure 9.

The proposed catalytic cycle of LigI, an enzyme catalyses the reversible hydrolysis of 2‐pyrone‐4,6‐dicarboxylate to 4‐oxalomesaconate and 4‐carboxy‐2‐hydroxymuconate in the degradation of lignin. The enzymatic reaction is independent to the presence of a metal ion.

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Further Reading

Frey PA and Hegeman AD (2007) Enzymatic Reaction Mechanisms, 1st edn. Oxford University Press. ISBN: 0195122585, 848 pages.

Petsko GA and Ringe D (2004) Protein Structure and Function. 1st edn. Sinauer Associates. Incorporated, ISBN: 0878936637, 195 pages.

Whitford D (2005) Proteins: Structure and Function, 1st edn. John Wiley & Sons, Ltd. ISBN: 978‐0‐471–49894‐0, 542 pages.

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How to Cite close
Liu, Aimin, and Huo, Lu(Aug 2014) Amidohydrolase Superfamily. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020546.pub2]