This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

This complex/polymer has been computationally inferred (based on PANTHER) from a complex/polymer involved in an event that has been demonstrated in another species.

EXO1 exonucleolytically degrades the strand being repaired in a 5' to 3' direction (Zhang et al. 2005, Orans et al. 2011, and inferred from EXO1 activity with MSH2:MSH6) to create a single -stranded gap extending 90-170 nucleotides beyond the insertion/deletion loop (IDL) (Fang and Modrich 1993). MLH1:PMS2 limits the length of excisions by EXO1 (Zhang et al. 2005). EXO1 also forms a complex with PCNA during S phase (Liberti et al. 2011). RPA binds the resulting single-stranded DNA (Lin et al. 1998, Ramilo et al. 2002, Zhang et al. 2005, reviewed in Iftode et al. 1999).

Because of their hydrophobicity, lipids are found in the extracellular spaces of the human body primarily in the form of lipoprotein complexes. Chylomicrons form in the small intestine and transport dietary lipids to other tissues in the body. Very low density lipoproteins (VLDL) form in the liver and transport triacylglycerol synthesized there to other tissues of the body. As they circulate, VLDL are acted on by lipoprotein lipases on the endothelial surfaces of blood vessels, liberating fatty acids and glycerol to be taken up by tissues and converting the VLDL first to intermediate density lipoproteins (IDL) and then to low density lipoproteins (LDL). IDL and LDL are cleared from the circulation via a specific cell surface receptor, found in the body primarily on the surfaces of liver cells. High density lipoprotein (HDL) particles, initially formed primarily by the liver, shuttle several kinds of lipids between tissues and other lipoproteins. Notably, they are responsible for the so-called reverse transport of cholesterol from peripheral tissues to LDL for return to the liver.

Three aspects of lipoprotein function are currently annotated in Reactome: chylomicron-mediated lipid transport, LDL endocytosis and degradation, and HDL-mediated lipid transport, each divided into assembly, remodeling, and clearance subpathways.

Very low-density lipoproteins (VLDLs) are produced in the liver to transport endogenous triglycerides, phospholipids, cholesterol, and cholesteryl esters in the hydrophilic environment of the bloodstream. They comprise triglycerides (50-60%), cholesterol (10-12%), cholesterol esters (4-6%), phospholipids (18-20%), and apolipoprotein B (8-12%). Of the protein content, two other apolipoproteins are constituents; apolipoprotein C-I (APOC around 20%) (Westerterp et al. 2007) and apolipoprotein C4 (APOC4, minor amount) (Kotite et al. 2003). After release from the liver, circulating VLDL particles can bind very low-density lipoprotein receptors (VLDLR) (Sakai et al. 1994) on extra-hepatic target cells and undergo endocytosis (Go & Mani 2012). VLDL uptake by VLDLR represents a minor contribution towards VLDL metabolism. The majority of VLDL is catalysed by lipoprotein lipase (LPL) which hydrolyses TAGs from VLDL, converting it to intermediate-density lipoprotein (IDL). IDL can be further hydrolysed by hepatic lipase to cholesterol-rich low-density lipoprotein (LDL).

VLDLR consists of five functional domains that resemble the LDL receptor. It is highly expressed in tissues that actively metabolise fatty acids as a source of energy. Binding of VLDLs to VLDLR appears to be inhibited by apolipoprotein C-I (APOC1), therby slowing the clearance of triglyceride-rich lipoproteins from the circulation (Westerterp et al. 2007). The APOE/C1/C4/C2 gene cluster is closely associated with plasma lipid levels, atherosclerotic plaque formation, and thereby implicated in the development of coronary artery disease and Alzheimer’s disease (Xu et al. 2015).

After being activated by an insertion/deletion loop (IDL), MSH2:MSH3 (MutSbeta) recruits MLH1:PMS2 (MutLalpha) (Iyer et al. 2010, Pluciennik et al. 2013) and interacts with PCNA (Iyer et al. 2010). As inferred from yeast, more than one molecule of MLH1:PMS2 may bind per molecule of MSH2:MSH3 (Hombauer et al. 2011). MLH1:PMS2 and PCNA compete for the same binding site on MSH2:MSH3 (Iyer et al. 2010). The interaction with PCNA determines which strand of DNA will serve as template and which strand will be repaired (Zhang et al. 2005, and inferred from MSH2:MSH6).

As chylomicrons circulate in the body, they acquire molecules of apolipoproteins C and E, and through interaction with endothelial lipases can lose a large fraction of their triacylglycerol. These changes convert them to chylomicron remnants which bind to LDL receptors, primarily on the surfaces of liver cells, clearing them from the circulation. This whole sequence of events is rapid: the normal lifespan of a chylomicron is 30 - 60 minutes (Redgrave 2004).
As they circulate, VLDL are acted on by lipoprotein lipases on the endothelial surfaces of blood vessels, liberating fatty acids and glycerol to be taken up by tissues and converting the VLDL first to intermediate density lipoproteins (IDL) and then to low density lipoproteins (LDL) (Gibbons et al. 2004).
HDL remodeling includes the conversion of HDL-associated cholesterol to cholesterol esters (remodeling of spherical HDL), the transfer of HDL lipids to target cells with the regeneration of pre-beta HDL (lipid-poor apoA-I), and the conversion of pre-beta HDL to discoidal HDL (Rye et al. 1999).

The mismatch repair (MMR) system corrects single base mismatches and small insertion and deletion loops (IDLs) of unpaired bases. MMR is primarily associated with DNA replication and is highly conserved across prokaryotes and eukaryotes. MMR consists of the following basic steps: a sensor (MutS homologue) detects a mismatch or IDL, the sensor activates a set of proteins (a MutL homologue and an exonuclease) that select the nascent DNA strand to be repaired, nick the strand, exonucleolytically remove a region of nucleotides containing the mismatch, and finally a DNA polymerase resynthesizes the strand and a ligase seals the remaining nick (reviewed in Kolodner and Marsischkny 1999, Iyer et al. 2006, Li 2008, Fukui 2010, Jiricny 2013).
Humans have 2 different MutS complexes. The MSH2:MSH6 heterodimer (MutSalpha) recognizes single base mismatches and small loops of one or two unpaired bases. The MSH2:MSH3 heterodimer (MutSbeta) recognizes loops of two or more unpaired bases. Upon binding a mismatch, the MutS complex becomes activated in an ATP-dependent manner allowing for subsequent downstream interactions and movement on the DNA substrate. (There are two mechanisms proposed: a sliding clamp and a switch diffusion model.) Though the order of steps and structural details are not fully known, the activated MutS complex interacts with MLH1:PMS2 (MutLalpha) and PCNA, the sliding clamp present at replication foci. The role of PCNA is multifaceted as it may act as a processivity factor in recruiting MMR proteins to replicating DNA, interact with MLH1:PMS2 and Exonuclease 1 (EXO1) to initiate excision of the recently replicated strand and direct DNA polymerase delta to initiate replacement of bases. MLH1:PMS2 makes an incision in the strand to be repaired and EXO1 extends the incision to make a single-stranded gap of up to 1 kb that removes the mismatched base(s). (Based on assays of purified human proteins, there is also a variant of the mismatch repair pathway that does not require EXO1, however the mechanism is not clear. EXO1 is almost always required, it is possible that the exonuclease activity of DNA polymerase delta may compensate in some situations and it has been proposed that other endonucleases may perform redundant functions in the absence of EXO1.) RPA binds the single-stranded region and a new strand is synthesized across the gap by DNA polymerase delta. The remaining nick is sealed by DNA ligase I (LIG1).
Concentrations of MMR proteins MSH2:MSH6 and MLH1:PMS2 increase in human cells during S phase and are at their highest level and activity during this phase of the cell cycle (Edelbrock et al. 2009). Defects in MSH2, MSH6, MLH1, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) (reviewed in Martin-Lopez and Fishel 2013).