Draft:Atglistatin

• Comment: This reads like a pharmaceutical company's market pitch. Drop phrasing like "stands out as the pioneering inhibitor" [bolding original]. Other sentences make me think this is an AI job: "Nowadays, science has got some of the tools that, through investigations, made it possible for experts to keep on developing and exploring how important this enzyme is biologically." Pbritti (talk) 13:39, 22 November 2023 (UTC)

• Comment: Please add better inline citations - the number should come directly after the claim that it supports. Currently, many of the in-text citations are misplaced. Thanks Ca ^{talk to me!} 13:30, 22 November 2023 (UTC)

• Comment: Please remove the bolding from body text. Pretty much the only thing that should be bolded is the first instance of the title term, at the start of the lead section. DoubleGrazing (talk) 11:01, 22 November 2023 (UTC)

• Comment: Why is this so promotional? DoubleGrazing (talk) 10:59, 22 November 2023 (UTC)

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3D structure of Atglistatin made with Biomodel

Atglistatin is an inhibitor that targets adipose triglyceride lipase (ATGL), the primary lipase responsible for initiating the breakdown of triglycerides into diglycerides. Subsequently, hormone-sensitive lipase (HSL) and monoglyceride lipase further degrade the diglycerides into glycerol and fatty acids, thereby fostering the synthesis of lipotoxic metabolites linked to the onset of insulin resistance (promoting the synthesis of lipotoxic metabolites associated with the development of insulin resistance).  Acting as the rate-limiting enzyme of ATGL, it plays a crucial role in the controlled release of fatty acids from cellular triglyceride stores.

The enzyme has no explicit activity against monoacylglycerol lipase (MGL), hormone-sensitive lipase (HSL), pancreatic lipase, or lipoprotein lipase (PNPLA6 and PNPLA7). Inhibition of ATGL by this enzyme has demonstrated a decrease in fatty acid mobilization both in vitro and in vivo.

Characteristics

Molecular weight	283.37 g /mol	2D structure of Atglistatin made with Biomodel
Solubility	20 mg/ml
Storage temperature	2-8ºC
Molecular formula	C17H21N3O
Chemical safety	Irritant
Synonyms	1469924-27-3, 3-(4'-(Dimethylamino) 1,1'-biphenyl]-3-yl)-1,1-dimethylurea, CHEMBL3823931, MFCD28009494

Adipose triglyceride lipase

Also recognized as patatin-like phospholipase domain-containing protein 2 and ATGL, this enzyme is encoded by the PNPLA2 gene. ATGL plays a pivotal role in the primary rate-limiting step of lipolysis, wherein it hydrolyses triacylglycerols stores in lipid droplets into diacylglycerols, targeting the fatty acid linked to carbon-3 of glycerol. Serving as a significant regulator of overall energy metabolism and plasma lipid levels, this process is present in both adipose and non-adipose tissues.

Insulin, a hormone produced by beta cells of the pancreatic islets and encoded by the insulin gene, regulates ATGL. In an inversely proportional relationship, as insulin levels decrease, ATGL levels increase. Adipose triglyceride lipase is also a key enzyme for maintaining a balance between mobilization and lipid storage, influencing regulatory functions such as cell death, growth, metabolism, gene expression, and others.

Operating mechanism (ATGL regulation)

ATGL’s catalytic site consists of a Serine-47 and an Aspartate-166 located in the patatin-like domain from the N-terminal half. The protein’s C-terminal zone contains a lipid droplet binding site. Mutations related to the lack of said C-terminal part can lead to harmful physiological alterations.

In humans, ATGL activates due to the union of Comparative Gene Identification-58 (CGI-58), which induces the functioning of the lipase. When it comes to natural inhibition we need the G0/G1 switch gene 2, which impedes the enzyme-substrate union, and a hypoxia-inducible gene 2 (HILPDA) that will bind to the patatin-like domain of the protein in order to inactivate it. Nonetheless, an inhibitor is being studied, it could be useful when it comes to the treatment and prevention of disorders such as cachexia, atherosclerosis, diabetes type II and conditions associated therewith. Kinetic studies have been conducted by the European Patent Office in order to investigate the inhibitor’s mechanism of action, and it has been revealed that Atglistatin is a competitive inhibitor. It causes an increase in the Km values and does not modify the Vmax. (view Fig. C in the article referenced above).

Implication in recent studies

Through investigations science has made it possible for experts to keep on developing and exploring the biological importance of this enzyme.

ATGL and cancer

Lipid metabolism plays a huge role in cancer. Cancer cells use LDs to ensure energy production and redox homeostasis, autophagy regulation, membrane synthesis, and composition control.

Oxygen availability in cells that are around the tumor tissue decreases as cell-vascular distance increases, meaning an anaerobic environment for the cell, and leading to hypoxia. As an adaptation, cancer cells change their metabolism from oxidative phosphorylation to glycolysis, which is known as the Warburg effect.

The hypoxic state of the tumor environment drives to reprogramming lipid metabolism in tumor cells. This state transforms ATGL into the enzyme regulator of the lipid metabolism, which gives the effect of proliferating or suppressing tumors depending on the type of cancer cell and the locus of tumorigenesis.

There is an important role for ATGL in LDs catabolism. Nevertheless, there is little data available to explain and understand the mechanisms by which ATGL might impact cancer formation and progression.

Recent studies in vivo clarified the situation and supported an antineoplastic role for ATGL. However, there are other studies that highlight that a downregulation of ATGL in cancer cells could induce an inflammatory microenvironment with drives to a proliferative signaling, in favor for cancer formation and progression.  

ATGL and energy homeostasis

ATGL has a significant importance when it comes to fatty acids and non-adipose tissues’ mobilization. In humans, loss-of-function mutations in either AGTL or its co-activator protein CGI-58 may lead to an excessive accumulation of lipids in multiple tissues, known as Neutral Lipid Storage Disease (NLSD). In many ATGL-deficient animals, under fasting conditions they can’t obtain energy from fatty acids to maintain their energy homeostasis and, in case their starving keeps getting worse, they induce a metabolic state characterized by decreased plasma fatty acids concentrations, hypoglycaemia, reduced oxygen consumption and hypothermia.

ATGL and cachexia

Another syndrome related to ATGL concentration is cachexia, a life-threatening syndrome related with an exponential loss of body weight, muscle atrophy, fatigue, weakness, and a significant loss of appetite which leads to asthenia, and anemia. It is quite common in cancer patients (50%) but it can also appear in certain infectious diseases such as tuberculosis and advanced organ failure. In this case, an ATGL deficiency could prevent patients from suffering cachexia, as it could stop the uncontrolled weight loss and increase cancer patients’ life expectancy.

External links

• Biomodel: Complementos de Bioquímica y Biología Molecular
• Atglistatin | ATGL Inhibitor