Metallo proteases, protease

According to their genetic relationship and their biochemical mechanism of action (3-lactamases are divided into enzymes of the serine-protease type containing an active-site serine (molecular class A, C, and D enzymes) and those of the metallo-protease type (molecular class B enzymes), which contain a complex bound zinc ion. 

Metallo proteases Exopeptidase group Peptidyl dipeptidase-A (ACE) Aminopeptidase-M Carboxypeptidase-A... 

Januario AH, Simone LS, Silvana M, et al. Neo-clerodane diterpenoid, a new metallo-protease snake venom inhibitor from Baccharis trimera (Asteraceae) anti-proteolytic and anti-hemorrhagic properties. Chem Biol Interact 2002 150 243-251. 

Human TNF-a is initially synthesized as a 233 amino acid polypeptide that is anchored in the plasma membrane by a single membrane-spanning sequence. This TNF pro-peptide, which itself displays biological activity, is usually proteolytically processed by a specific extracellular metallo-protease. Proteolytic cleavage occurs between residues 76 (Ala) and 77 (Val), yielding the mature (soluble) 157 amino acid TNF-a polypeptide. Mature human TNF-a appears to be devoid of a carbohydrate component, and contains a single disulfide bond. 

Protease 3D structural models matrix metallo protease-inhibitor complexes... 

Very recently, (3-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15] in addition, the discoveries of new biologically active (3-lactams such as cholesterol acyl transferase inhibitors [16-18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new (3-lactam systems. 

Peterson JT, Li H, Dillon L, Bryant JW. Evolution of metallo-protease and tissue inhibitor expression during heart failure progression in the infarcted heart, Cardiovasc Res 2000 46 307-315. 

The human plasma metallo-protease carboxypeptidase N (CPN, arginine... 

Metallo- protease collagenase (mammalian) cleaves a Gly-Leu or Gly-Ile bond in native triple helical collagen... 

Numerous reversible inhibitors have been developed for metallo-proteases and some have therapeutic applications. 

Figure 1.12 The arylsulfonylhydroxamate scaffold (top) served as template structure for compounds active on various members of the matrix metallo-protease family, as well as of phosphodiesterase 4. By variation of the molecular periphery (R-groups, X top), discriminating compounds (bottom left, bottom middle), as well as dual inhibitors (bottom right) were obtained [61, 62].

Neurotoxins, such as the clostridial neurotoxins responsible for tetanus and botulism. These are metallo-proteases that enter nerve cells and block neurotransmitter release via zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. 

ADAM. A Disintesrin And MetalloProteinase family of proteins. Disintegrins, as the name implies, are proteins which interfere with interactions of cells with proteins in the extracellular matrix. An example are the inhibitors of the interaction of blood platelets with fibrinogen. Disintegrins are found in snake venom. Metalloproteinases are a family of proteases which need a bivalent cation for catalysis. MMP s are matrix metallo-proteases. They are associated with the extracellular matrix. 

The reader is referred to the original papers for an account of the spectroscopic procedures. The most significant findings are in Tables II and III [taken from Hunkapiller et al. (32)]. The pAytic protease listed in Table II is another enzyme of Myxobacter 495, a metallo-protease with eight histidine residues. 

The fS-lactamases have mirrored the chemical strategy of proteases to cleave the fS-lactam bond. The main fS-lactamase families emulate Ser or metallo-protease mechanisms to perform ring-opening hydrolysis of the fS-lactam ring, destroying the antibiotic warhead in the process (Fig. 6). The Ser enzymes mimic the first step in peptidoglycan transpeptidase reaction by formation of an acyl-enzyme intermediate. However, unlike the transpeptidase, this intermediate is short lived and subsequent hydrolysis releases the inactive antibiotic (Fig. 6). 

Similarly, metallo- 3-lactamases share with metallo-proteases activation of a hydrolytic water molecule by interaction with an active-site Zn + ion. These lactamases have gained clinical prominence in the past few years as a result of their association with carbapenem resistance. The carbapenems, such as meropenem and imipenem, are fS-lactam antibiotics that have been introduced to circumvent Ser-fS-lactamase activity. The trans stereochemistry across the 6-5 bond rather than the cis geometry found in most other fS-lactams (Fig. 7) contributes to... 

Figure 6 p-Lactamases hydrolytically cleave the susceptible p-lactam ring using Ser and metallo-protease mode chemistry. 

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