Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.1.4 (
deaminase
)
5,113
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well-defined, only recently has the molecular basis of reversible polyamine acetylation been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized:
histone deacetylase 10
(
HDAC10
) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N
8
-acetylspermidine deacetylase, and its prokaryotic counterpart, acetylpolyamine
amidohydrolase
(APAH) from Mycoplana ramosa, is a broad-specificity polyamine deacetylase. Similar to the greater family of HDACs, which mainly serve as lysine deacetylases, both enzymes adopt the characteristic arginase-deacetylase fold and employ a Zn
2+
-activated water molecule for catalysis. In contrast with HDACs, however, the active sites of
HDAC10
and APAH are sterically constricted to enforce specificity for long, slender polyamine substrates and exclude bulky peptides and proteins containing acetyl-l-lysine. Crystal structures of APAH and D. rerio
HDAC10
reveal that quaternary structure, i.e., dimer assembly, provides the steric constriction that directs the polyamine substrate specificity of APAH, whereas tertiary structure, a unique 3
10
helix defined by the P(E,A)CE motif, provides the steric constriction that directs the polyamine substrate specificity of
HDAC10
. Given the recent identification of
HDAC10
and spermidine as mediators of autophagy,
HDAC10
is rapidly emerging as a biomarker and target for the design of isozyme-selective inhibitors that will suppress autophagic responses to cancer chemotherapy, thereby rendering cancer cells more susceptible to cytotoxic drugs.
...
PMID:Polyamine Deacetylase Structure and Catalysis: Prokaryotic Acetylpolyamine Amidohydrolase and Eukaryotic HDAC10. 2953 2
Polyamines are small organic cations that are essential for cellular function in all kingdoms of life. Polyamine metabolism is regulated by enzyme-catalyzed acetylation-deacetylation cycles in a fashion similar to the epigenetic regulation of histone function in eukaryotes. Bacterial polyamine deacetylases are particularly intriguing, because these enzymes share the fold and function of eukaryotic histone deacetylases. Recently, acetylpolyamine
amidohydrolase
from the deep earth halophile
Marinobacter subterrani
(msAPAH) was described. This Zn
2+
-dependent deacetylase shares 53% amino acid sequence identity with the acetylpolyamine
amidohydrolase
from
Mycoplana ramosa
(mrAPAH) and 22% amino acid sequence identity with the catalytic domain of
histone deacetylase 10
from
Danio rerio
(zebrafish; zHDAC10), the eukaryotic polyamine deacetylase. The X-ray crystal structure of msAPAH, determined in complexes with seven different inhibitors as well as the acetate coproduct, shows how the chemical strategy of Zn
2+
-dependent amide hydrolysis and the catalytic specificity for cationic polyamine substrates is conserved in a subterranean halophile. Structural comparisons with mrAPAH reveal that an array of aspartate and glutamate residues unique to msAPAH enable the binding of one or more Mg
2+
ions in the active site and elsewhere on the protein surface. Notwithstanding these differences, activity assays with a panel of acetylpolyamine and acetyllysine substrates confirm that msAPAH is a broad-specificity polyamine deacetylase, much like mrAPAH. The broad substrate specificity contrasts with the narrow substrate specificity of zHDAC10, which is highly specific for
N
8
-acetylspermidine hydrolysis. Notably, quaternary structural features govern the substrate specificity of msAPAH and mrAPAH, whereas tertiary structural features govern the substrate specificity of zHDAC10.
...
PMID:Structure and Function of the Acetylpolyamine Amidohydrolase from the Deep Earth Halophile
Marinobacter subterrani
. 3143 69
